Novel tricyclic chiral compounds and their use in asymmetric catalysis

ABSTRACT

The present invention relates to a compound of general Formula (VIII), 
     
       
         
         
             
             
         
       
     
     the compound having a bowl-shaped conformation, its formation and its use in asymmetric catalysis. In Formula (VIII), M is a metal selected from the group consisting of Group 1 to Group 14 metals, lanthanides and actinides; R is one of —COOR 3 , —R 4 COOR 3 , —R 4 CHO, —R 4 COR 3 , —R 4 CONR 5 R 6 , —R 4 COX, —R 4 OP(═O)(OH) 2 , —R 4 P(═O)(OH) 2 ), —R 4 C(O)C(R 3 )CR 5 R 6  and R 4 CO 2 C(R 3 )O, wherein R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are as defined herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 13/062,193, filed Jul. 22, 2011, currently pending, which is a 371filing of International Application No. PCT/SG2009/000312, filed Sep. 3,2009 which claims the benefit of priority of U.S. Provisional AppicationNo. 61/093,843, filed Sep. 3, 2008, which applications are incorporatedherein by reference in their entiries.

FIELD OF THE INVENTION

The present invention relates to novel tricyclic chiral compounds andtheir use in asymmetric catalysis. The tricyclic chiral compounds have ahexahydropyrrolo[2,3-b]-indole skeleton.

BACKGROUND

Driven by the ever-increasing demand for chiral chemicals, thedevelopment of new and efficient methods to provide enantioenrichedproducts is of great interest to both academia and industry. Catalyticasymmetric reactions using organocatalysts provide one of the mostpowerful and economical synthetic approaches to a variety ofenantiomerically enriched compounds. The development of new privilegedchiral ligands and catalysts that exhibit high reactivity andenantioselectivity is always a challenging endeavour for an organicchemist. State-of-the-art chiral ligands generally come from theprofound understanding of catalytic process, the creativity of organicchemists and sometimes, a degree of serendipity. The most importantfeature of privileged chiral catalysts is the highly rigid structures,with multiple oxygen-, nitrogen-, or phosphorous-containing functionalgroups to bind strongly to reactive metal centers [e.g. Yoon, T P, &Jacobsen, E N, Science (2003) 299, 1691-1693 or Pfaltz, A, & Drury III,W J, PNAS (2004) 101, 5723-5726]. Another important point is that itshould be easily prepared and modified, thus fit well to a combinatorialapproach for finding the most suitable ligand for a particular catalyticasymmetric transformation. A compound that has been ascribed as a“universal catalyst” due to its widespread application inorganocatalysis is proline, However, it is widely accepted that prolineis usually not an efficient catalyst in terms of yield andenantioselectivity for electrophiles that are poor hydrogen bondacceptors such as nitroalkenes.

Unfortunately, with most organocatalysts for asymmetric catalysis theuse of high catalytic loading (>10 mol %), the need to use anhydrousorganic solvents or/and the narrow substrate scope limit theirapplicability to complex molecule synthesis. Furthermore, theorganocatalyzed functionalization of biomolecules in water remains achallenge.

Therefore, there remains a need for novel organocatalysts. It would alsobe particularly useful to provide an organocatalyst which can worknicely in both water and organic solvents.

SUMMARY OF THE INVENTION

The invention relates to a novel class of structurally rigid tricyclicchiral compounds based on hexahydropyrrolo[2,3-b]indole skeleton whichcan be synthesized from a L-tryptophan derivative in five steps. Theligands can be used for example as an efficient chiral ligand in theenantioselective borane reduction of prochiral ketones to afford thecorresponding alcohols in excellent yield and high enantioselectivities,or in enatioselective carbon-carbon bond formation.

In a first aspect the invention provides a hexahydropyrrolo[2,3-b]indolecompound of Formula (XX):

In Formula (XX) R is one of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³,—R⁴CONR⁵R⁶, —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂), R⁴C(O)C(R³)CR⁵R⁶,—R⁴CO₂COR³ and (R³CO)₂O. R³¹ is one of hydrogen, —COOR³, —R⁴COOR³,—R⁴CHO, —R⁴COR³, —R⁴CONR⁵R⁶, —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂),—R⁴C(O)C(R³)CR⁵R⁶, —R⁴CO₂COR³ and (R³CO)₂O. R³, R⁵ and R⁶ areindependent from one another one of hydrogen, an aliphatic group with amain chain having 1 to about 20 carbon atoms, an alicyclic group, anaromatic group, an arylaliphatic group and an arylalicyclic group,comprising 0 to about 3 heteroatoms. The heteroatoms are independentlyselected from N, O, S, Se and Si. R⁴ is one of an aliphatic bridge witha main chain having 1 to about 20 carbon atoms, an alicyclic bridge, anaromatic bridge, an arylaliphatic bridge and an arylalicyclic bridge,comprising 0 to about 3 heteroatoms. The heteroatoms are independentlyselected from N, O, S, Se and Si, X is halogen, Further, in Formula (XX)R³⁰ is one of —C(OH)R¹R² and —COOR¹⁴. R¹, R² and R¹⁴ are independentfrom one another one of hydrogen, an aliphatic group with a main chainhaving 1 to about 20 carbon atoms, an alicyclic group, an aromaticgroup, an arylaliphatic group and an arylalicyclic group, comprising 0to about 3 heteroatoms. The heteroatoms are independently selected fromN, O, S, Se and Si.

In a second aspect the invention provides ahexahydropyrrolo[2,3-b]indole compound of Formula (VII):

In Formula (VII) R is one of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³,—R⁴CONR⁵R⁶, —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂), —R⁴C(O)C(R³)CR⁵R⁶,—R⁴CO₂COR³ and —(R³CO)₂O. R³ is one of hydrogen, (C₁-C₂₀)-alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl,alkylaryl, and arylalkyl. R⁴ is one of hydrogen, (C₁-C₂₀)-alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl,alkylaryl, and arylalkyl. R⁵ is one of hydrogen, (C₁-C₂₀)-alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl,alkylaryl, and arylalkyl. R⁶ is one of hydrogen, (C₁-C₂₀)-alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl,alkylaryl, and arylalkyl. X is halogen. In some embodiments R³ to R⁶ areindependent from one another one of hydrogen, (C₁-C₁₀) alkyl, (C₃-C₅)cycloalkyl, (C₁-C₃) alkylaryl, arylalkyl, where the alkyl radicals, maybe substituted by one or more substituents,for example, —OH,—O—(C₁-C₁₀)-alkyl, —O-phenyl, —O—CO—(C₁-C₁₀)-alkyl, —O—CO-aryl,—CO—(C₁-C₅)-alkyl, —CO—O—(C₁-C₅)-alkyl, —CO—O-aryl, and aryl. Further,in Formula (VII) R¹ is independently selected from hydrogen,(C₁-C₂₀)-alkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, alkylaryl, and arylalkyl heteroaryl. Alkyl, alkenyl oralkynyl can be straight chained or branched, and may be substituted byone or more substituents. R² in Formula (VII) is independently selectedfrom hydrogen, (C₁-C₂₀)-alkyl, aryl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkylalkyl, alkylaryl, arylalkyl, and heteroaryl.Alkyl, alkenyl or alkynyl can be straight chained or branched, and maybe substituted by one or more substituents. R¹ and R² may in someembodiments be independent from one another one of hydrogen,(C₁-C₁₀)-alkyl, (C₃-C₈) cycloalkyl, (C₁-C₃) alkylaryl, arylalkyl aryl,or heteroaryl. Again, the alkyl radicals, may be branched andsubstituted by one or more substituents, for example by —OH,—O—(C₁-C₁₀)-alkyl, —O-phenyl, —O—CO—(C₁-C₁₀)-alkyl, —O—CO-aryl,—CO—(C₁-C₅)-alkyl, —CO—O—(C₁-C₅)-alkyl, —CO—O-aryl.

In a third aspect the invention provides a hexahydropyrrolo[2,3-b]indolecompound of Formula (VIII):

The compound of Formula (VIII) has a bowl-shaped conformation. InFormula (VIII) M is a metal selected from the group consisting of Group1 to Group 14 metals, lanthanides and actinides. Further, in Formula(VIII) the moiety R is one of COOR³, R³COOR⁴, R³CHO, R³COR⁴, R³CONR⁴R⁵,R³COX, R³OP(═O)(OH)₂, R³P(═O)(OH)₂), R³C(O)C(R⁴)CR⁵R⁶, —R⁴CO₂COR³ and(R³CO)₂O. R³ is one of hydrogen, (C₁-C₂₀)-alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, alkylaryl, orarylalkyl. R⁴ is one of hydrogen, (C₁-C₂₀)-alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, alkylaryl, andarylalkyl. R⁵ is one of hydrogen, (C₁-C₂₀)-alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, alkylaryl, orarylalkyl. R⁶ is one of hydrogen, (C₁-C₂₀)-alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, alkylaryl, andarylalkyl. X is halogen. Further, in Formula (VIII) R¹ is independentlyselected from hydrogen, (C₁-C₂₀)-alkyl, aryl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkylaryl, and arylalkylheteroaryl. Alkyl, alkenyl or alkynyl can be straight chained orbranched, and may be substituted by one or more substituents. R² inFormula (VIII) is independently selected from hydrogen, (C₁-C₂₀)-alkyl,aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,alkylaryl, arylalkyl, and heteroaryl. Alkyl, alkenyl or alkynyl can bestraight chained or branched, and may be substituted by one or moresubstituents.

In a fourth aspect the invention provides ahexahydropyrrolo[2,3-b]indole compound of Formula (IX):

The compound of Formula (IX) has an S-shaped conformation. In Formula(IX) M is a metal selected from the group consisting of Group 1 to Group14 metals, lanthanides and actinides. Further, in Formula (IX) R is oneof COOR³, R³COOR⁴, R³CHO, R³COR⁴, R³CONR⁴R⁵, R³COX, R³OP(═O)(OH)₂,R³P(═O)(OH)₂) R³C(O)C(R⁴)CR⁵R⁶ , —R⁴CO₂COR³ and (R³CO)₂O. R³ is one ofhydrogen, (C₁-C₂₀)-alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, aryl, alkylaryl, or arylalkyl. R⁴ is one of hydrogen,(C₁-C₂₀)-alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, aryl, alkylaryl, and arylalkyl. R⁵ is one of hydrogen,(C₁-C₂₀)-alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, aryl, alkylaryl, or arylalkyl. R⁶ is one of hydrogen,(C₁-C₂₀)-alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, aryl, alkylaryl, and arylalkyl. X is halogen. Further,in Formula (IX) R¹ is independently selected from hydrogen,(C₁-C₂₀)-alkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, alkylaryl, and arylalkyl heteroaryl. Alkyl, alkenyl oralkynyl can be straight chained or branched, and may be substituted byone or more substituents. R² in Formula (IX) is independently selectedfrom hydrogen, (C₁-C₂₀)-alkyl, aryl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkylalkyl, alkylaryl, arylalkyl, and heteroaryl.Alkyl, alkenyl or alkynyl can be straight chained or branched, and maybe substituted by one or more substituents.

In a fifth aspect the invention provides a hexahydropyrrolo[2,3-b]indolecompound of Formula (VI):

In Formula (VI) R is one of COOR³, R³COOR⁴, R³CHO, R³COR⁴, R³CONR⁴R⁵,R³COX, R³OP(═O)(OH)₂, R³P(═O)(OH)₂) R³C(O)C(R⁴)CR⁵R⁶, —R⁴CO₂COR³ and(R³CO)₂O. R³ is one of hydrogen, (C₁-C₂₀)-alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, alkylaryl, orarylalkyl. R⁴ is one of hydrogen, (C₁-C₂₀)-alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, alkylaryl, andarylalkyl. R⁵ is one of hydrogen, (C₁-C₂₀)-alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, alkylaryl, orarylalkyl. R⁶ is one of hydrogen, (C₁-C₂₀)-alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, alkylaryl, andarylalkyl. X is halogen. R⁹ in Formula (VI) is alkyl.

In a sixth aspect the invention provides a hexahydropyrrolo[2,3-b]indolecompound of Formula (IV):

In Formula (IV) R is one of COOR³, R³COOR⁴, R³CHO, R³COR⁴, R³CONR⁴R⁵,R³COX, R³OP(═O)(OH)₂ , R³P(═O)(OH)₂) R³C(O)C(R⁴)CR⁵R⁶, —R⁴CO₂COR³ and(R³CO)₂O. R³ is one of hydrogen, (C₁-C₂₀)-alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, alkylaryl, orarylalkyl. R⁴ is one of hydrogen, (C₁-C₂₀)-alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, alkylaryl, andarylalkyl. R⁵ is one of hydrogen, (C₁-C₂₀)-alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, alkylaryl, orarylalkyl. R⁶ is one of hydrogen, (C₁-C₂₀)-alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, alkylaryl, andarylalkyl. X is halogen. Y in Formula (IV) is a nitrogen protectinggroup. R⁹ in Formula (IV) is alkyl.

In a seventh aspect the invention provides ahexahydropyrrolo[2,3-b]indole compound of Formula (IVA):

In Formula (IVA) R is one of COOR³, R³COOR⁴, R³CHO, R³COR⁴, R³CONR⁴R⁵,R³COX, R³OP(═O)(OH)₂, R³P(═O)(OH)₂) R³C(O)C(R⁴)CR⁵R⁶, —R⁴CO₂COR³ and(R³CO)₂O. R³ is one of hydrogen, (C₁-C₂₀)-alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, alkylaryl, orarylalkyl. R⁴ is one of hydrogen, (C₁-C₂₀)-alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, alkylaryl, andarylalkyl. R⁵ is one of hydrogen, (C₁-C₂₀)-alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, alkylaryl, orarylalkyl. R⁶ is one of hydrogen, (C₁-C₂₀)-alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, alkylaryl, andarylalkyl. X is halogen. Y in Formula (IVA) is a nitrogen protectinggroup. R¹⁰ in Formula (IVA) is a protecting group that may be removableby hydrogenolysis, e.g. aryl-methylenyl.

In an eigth aspect the invention provides ahexahydropyrrolo[2,3-b]indole compound of Formula (VIA):

In Formula (VIA) R is one of COOR³, R³COOR⁴, R³CHO, R³COR⁴, R³CONR⁴R⁵,R³COX, R³OP(═O)(OH)₂, R³P(═O)(OH)₂) R³C(O)C(R⁴)CR⁵R⁶, —R⁴CO₂COR³ and(R³CO)₂O. R³ is one of hydrogen, (C₁-C₂₀)-alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, alkylaryl, orarylalkyl. R⁴ is one of hydrogen, (C₁-C₂₀)-alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, alkylaryl, andarylalkyl. R⁵ is one of hydrogen, (C₁-C₂₀)-alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, aryl, alkylaryl, orarylalkyl. R⁶ is one of hydrogen, (C₁-C₂₀)-alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cyclo-alkylalkyl, aryl, alkylaryl, andarylalkyl. X is halogen.

In a nineth aspect the invention provides a method of preparing acompound of

Formula (VI) according to the fifth aspect (supra). The method includesproviding a compound of Formula (IV) according to the sixth aspect(supra). Moiety Y in the compound of Formula (VI) is generally cleavablevia hydrogenolysis. The method includes exposing the compound of Formula(IV) to H₂ in the presence of a Pd/C catalyst. Thereby the methodincludes allowing deprotection of the Nα group of compound (IV).

In a tenth aspect the invention provides a method of preparing acompound of Formula (VIA) according to the eigth aspect (supra). Themethod includes providing a compound of Formula (IVA) according to theseventh aspect (supra). As said above, generally (but not necessarily)moiety Y in the compound of Formula (IVA) is cleavable viahydrogenolysis. The method further includes exposing the compound ofFormula (IVA) to H₂ in the presence of a Pd/C catalyst. Thereby themethod firstly includes allowing deprotection of the Nα group ofcompound (IV A). The method thereby secondly also includes allowing thecleavage of the ester bond to moiety R¹⁰ of compound IVA).

In an eleventh aspect the invention provides a method of preparing acompound of Formula (VII) according to the second aspect (supra). Themethod includes reacting a compound of Formula (VI) according to thefifth aspect (supra) with a compound R¹MgX, R²MgX or a mixture of R¹MgXand R²MgX. R¹ in R¹MgX is independently selected from hydrogen,(C₁-C₂₀)-alkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkylalkyl, alkylaryl, and arylalkyl heteroaryl. R² in R²MgX isindependently selected from hydrogen, (C₁-C₂₀)-alkyl, aryl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, alkylaryl,arylalkyl, and heteroaryl.

In a twelfth aspect the invention provides a method of preparing acompound of Formula (IV) according to the sixth aspect (supra). Themethod includes contacting a hexahydropyrrolo[2,3-b]indole compound ofFormula (III)

with an acyl halide RCOX in the presence of a base. In Formula (III) Yis a nitrogen protecting group, and R⁹ is alkyl.

In a thirteenth aspect the invention provides a method of preparing acompound of Formula (IVA) according to the seventh aspect (supra). Themethod includes contacting a hexahydropyrrolo[2,3-b]indole compound ofFormula (IIIA)

with an acyl halide RCOX in the presence of a base. In Formula (IIIA) Yis a nitrogen protecting group, and R¹⁰ is aryl-methylenyl.

In a fourteenth aspect the invention provides a method of preparing acompound of Formula (VIII) according to the third aspect (supra). Themethod includes reacting a compound of Formula (VII) according to thesecond aspect with a metal compound selected from the group consistingof Group 1 to Group 14 metals, lanthanides and actinides.

In a fifteenth aspect the invention provides a method of preparing acompound of Formula (IX) according to the fourth aspect (supra). Themethod includes reacting a compound of Formula (VII) according to thesecond aspect with a metal compound selected from the group consistingof Group 1 to Group 14 metals, lanthanides and actinides.

In a sixteenth aspect the invention provides the use of the compound ofFormulas (VII), (VIII), (IX), (IV) and (VI) according to the second tothe sixth aspects as a ligand for asymmetric catalysis.

In a seventeenth aspect the invention provides the use of the compoundof Formula (VIA) according to the nineth aspect (supra) as a ligand forasymmetric catalysis.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be better understood with reference to the detaileddescription when considered in conjunction with the non-limitingexamples and the accompanying drawings.

FIG. 1 compares the structures of two exemplary compounds of theinvention, a compound of Formula VII and a compound of Formula (VIA),and of some natural products with hexahydropyrrolo[2,3-b]indoleskeleton.

FIG. 2 depicts schematically the synthesis of a compound of Formula(VII), starting from a commercially available Na-protected L-tryptophan(1).

FIG. 3 depicts schematically the synthesis of a compound of Formula(VIA), starting from a commercially available Na-protected L-tryptophan(1).

FIG. 4A depicts an illustrative example of a compound of Formula (VI)together with a schematic of its X-ray structure. FIG. 4B depicts anillustrative example of a compound of Formula (VII) together with aschematic of its X-ray structure.

FIG. 5 illustrates the use of a compound of Formula (VII) in theasymmetric reduction of a ketone.

FIG. 6 depicts the two different isomers of metal complexes exemplifiedby a compound of Formula (VIII) with R¹=R²=ph, and a compound of Formula(IX) together with a 3D model thereof.

FIG. 7 illustrates the potential of design of structurally rigid chiralligands based on the general structure of a compound of Formula (VIII).

FIG. 8A illustrates the use of a compound of Formula (VIA) in acatalytic asymmetric Michael addition with the Michael acceptor being anitro group. FIG. 8B illustrates the use of a compound of Formula (VIA)in a catalytic asymmetric Michael addition with the Michael acceptorbeing a carbonyl group. FIG. 8C illustrates the use of a compound ofFormula (VIA) in a catalytic asymmetric Michael addition with theMichael acceptor being a nitro group. FIG. 8D depicts the use of acompound of Formula (VIA) in a catalytic asymmetric Michael additionwith the Michael acceptor being a sulfonyl group. FIG. 8E and FIG. 8Fillustrate experimental examples on the use of a compound of Formula(VIA) in a catalytic asymmetric Michael addition (CAN in FIG. 8Frepresents ceric ammonium nitrate (NH₄)₂Ce(NO₃)₆). FIG. 8G depicts thepreliminary result of an experimental example that may indicate anexception from the general applicability of the catalytic asymmetricMichael addition according to the invention or that may be difficult tocarry out. FIG. 8H depicts further examples of compounds for whichpreliminary data indicate their suitability as Michael acceptors.

FIG. 9A depicts the most stable conformation of the enamineintermediate, a syn conformation, by DFT calculation. FIG. 9B depictsthe lowest energy transition state (XXXA) for this reaction by DFTcalculation. FIG. 9C depicts a theoretical alternative transition state(XXXB) that does not involve a water molecule.

FIG. 10A depicts ¹HNMR spectra showing the salt formation of (10) andDMAP (CD₃OD). FIG. 10B depicts ¹HNMR spectra showing the stability ofcatalyst (10) in water (D₂O). No peak change and chemical shift changeoccurred even after 32 days. FIG. 10C depicts ¹HNMR spectra showing thestability of catalyst (10)/DMAP in water (D₂O). No peak change andchemical shift change occurred even after 20 days.

FIG. 11 is a table depicting exemplary data on the catalytic asymmetricreduction of ketones. Reactions were performed with 0.5 mmol ketone, 0.6mmol borane, 10% of the respective ligand in 2 mL THF at refluxtemperature. ^(a) Isolated yield by column chromatography. ^(b) eedetermined by HPLC analysis using a Daicel Chiralcel AS-H column.

FIG. 12A is a table depicting exemplary data on optimizations of theenantioselective borane reduction of Acetonaphthone according to a useof the present invention. Reactions were performed with 0.5 mmolacetonaphthone, 0.6 mmol borane, 10% of the respective ligand in 2 mL ofsolvent at reflux temperature. ^(a) Isolated yield by columnchromatography. ^(b) ee determined by HPLC analysis using a DaicelChiralcel AS-H column. ^(c) Catalyst prepared by 0.1 eq ligand with 0.12eq B(OMe)₃ at RT and reduction at RT. ^(d) Catalyst prepared by 0.1 eqligand with 0.12 eq B(OMe)₃ at reflux condition and reduction at refulxcondition. ^(e) Ligand was was recycled once. ^(f) Ligand was recycledtwice ^(g) Ligand was recycled third time. FIG. 12B depicts furtherexamples of compounds that were tested in the enantioselective boranereduction and the observed yields and ee.

FIG. 13A depicts exemplary catalysts used in the asymmetric Michaelreaction of propanal to nitroalkenes depicted in the scheme of FIG. 13B.FIG. 13C is a table depicting exemplary data on the catalytic asymmetricMichael addition of FIG. 13B. Reactions were conducted with 2 equiv ofaldehyde, 1 equiv of nitrostyene at room temperature in the presence ofcatalyst with 1:1 catalyst:DMAP. ^(a) Isolated yield. ^(b) Dr (syn/anti)was determined by chiral HPLC analysis. ^(c) Reported values refer tothe syn isomer and were determined by chiral HPLC on a chiral stationaryphase. FIG. 13D depicts a further asymmetric Michael reaction, the (10)catalysed addition of isovaler-aldehyde to vinyl sulphone.

FIG. 14 is a table depicting exemplary data on the catalytic asymmetricMichael addition of unmodified aldehydes to Nitroalkenes. Reactions wereconducted with 2 equiv of aldehyde, 1 equiv of nitrostyene at roomtemperature or 4 equiv of aldehyde at 60° C. (for bulky aldehydes inentries 12-14), in the presence of catalyst with 1:1 catalyst/DMAP.Generally 0.2 mmol nitroalkene, 0.4 mmol aldehyde were used at roomtemperature and 0.2 mmol nitroalkene, 0.8 mmol aldehyde at 60° C. ^(a)Isolated yield. ^(b) Dr was determined by chiral HPLC analysis afterpurification ^(c) Reported values refer to the syn isomer and weredetermined by chiral HPLC on a chiral stationary phase. Cy in entry 6means cyclohexyl.

FIG. 15 depicts schematically the preparation and characterization ofexemplary chiral ligands of Formula VII, starting from a commerciallyavailable Nα-protected L-tryptophan (1) (cf. also FIG. 2).

FIG. 16 shows graphically the results of X-Ray crystal data analysis ofa nitroalkane product obtained in a Michael addition using a compound ofthe invention (see Examples for the X-Ray crystal data).

FIG. 17 shows graphically the results of X-Ray crystal data analysis ofa compound of the invention of general Formula (VI) (cf. also FIG. 4Aand the Examples below).

FIG. 18 shows graphically the results of X-Ray crystal data analysis ofa compound of the invention of general Formula (VII) (cf. also FIG. 4Aand the Examples below).

FIG. 19 depicts chiral HPLC analysis of racemic 1-phenylethanol on aDacicel Chiralcel OD column as a reference (cf. FIG. 20).

FIG. 20 depicts chiral HPLC analysis of (R)-1-phenylethanol obtainedusing a catalyst of general Formula (VII) on a Dacicel Chiralcel ODcolumn.

FIGS. 21A, 21B and 21C depict chiral HPLC analysis of(S)-2-Bromo-1-phenylethanol obtained using a catalyst of general Formula(VII) on a Dacicel Chiralcel OD column (FIG. 21C corresponding to FIG.21A).

FIGS. 22A, 22B, 22C and 22D depict chiral HPLC analysis of(R)-1-(4-Bromophenyl)-ethanol obtained using a catalyst of generalFormula (VII) on a Dacicel Chiralcel OB-H column (FIG. 22B correspondingto FIG. 22A and FIG. 22D corresponding to FIG. 22C).

FIGS. 23A, 23B, 23C and 23D depict chiral HPLC analysis of(R)-1-(2-Naphthyl)-ethanol obtained using a catalyst of general Formula(VII) on a Dacicel Chiralcel AS-H column column.

FIGS. 24A, 24B, 24C and 24D depict chiral HPLC analysis of(R)-1-(2-(6-methoxy)-Naphthyl)-ethanol obtained using a catalyst ofgeneral Formula (VII) on a Dacicel Chiralcel OD column.

FIGS. 25A and 25B depict chiral HPLC analysis of racemic1-(4-Nitrophenyl)-ethanol on a Chiralcel OB-H column as a reference.

FIGS. 26A and 26B depict chiral HPLC analysis of(R)-1-(4-Nitrophenyl)-ethanol obtained using a catalyst of generalFormula (VII) on a Chiralcel OB-H column.

FIGS. 27A, 27B, 27C and 27D depict chiral HPLC analysis of(R)-1-(3-fluorophenyl)-ethanol obtained using a catalyst of generalFormula (VII) on a Chiralcel OB-H column.

FIGS. 28A, 28B, 28C and 28D depict chiral HPLC analysis of(R)-1-(4-Trifluoromethylphenyl)-ethanol obtained using a catalyst ofgeneral Formula (VII) on a Chiralcel OJ column.

FIGS. 29A and 29B depict chiral HPLC analysis of racemic1-(3-Trifluoromethylphenyl)-ethanol obtained using a catalyst of generalFormula (VII) on a Chiralcel OBH column as a reference (cf. FIG. 30A andFIG. 30B).

FIGS. 30A and 30B depict chiral HPLC analysis of(R)-1-(3-Trifluoromethylphenyl)-ethanol obtained using a catalyst ofgeneral Formula (VII) on a Chiralcel OBH column.

FIGS. 31A, 31B, 31C and 31D depict chiral HPLC analysis of(R)-1-(4-methylsulfonylphenyl)ethanol obtained using a catalyst ofgeneral Formula (VII) on a Chiralcel OBH column.

FIGS. 32A, 32B, 32C and 32D depict chiral HPLC analysis of(R)-1-(3,5-difluorophenyl)ethanol obtained using a catalyst of generalFormula (VII) on a Chiralcel OB-H column.

FIGS. 33A, 33B, 33C and 33D depict chiral HPLC analysis of(R)-3,5-bistrifluoromethylphenyl ethanol obtained using a catalyst ofgeneral Formula (VII) on a Chiralcel OB-H column.

FIGS. 34A, 34B, 34C and 34D depict chiral HPLC analysis of(R)-1-(3,4-difluorophenyl)ethanol obtained using a catalyst of generalFormula (VII) on a Chiralcel OB-H column.

FIG. 35 depicts a further theoretically possible conformation of theenamine intermediate, a syn conformation that was compared in DFTcalculation (cf. the Examples below).

FIG. 36 depicts a further theoretically possible conformation of theenamine intermediate, a syn conformation that was compared in DFTcalculation (cf. the Examples below).

FIG. 37 depicts a further theoretically possible conformation of theenamine intermediate, an anti conformation that was compared in DFTcalculation (cf. the Examples below).

FIG. 38 depicts a further theoretically possible conformation of theenamine intermediate, an anti conformation that was compared in DFTcalculation (cf. the Examples below).

FIG. 39 depicts a theoretically possible conformation of the transitionstate that was compared in DFT calculation (cf. the Examples below).

DETAILED DESCRIPTION OF INVENTION

The present invention relates to the design and synthesis of a series ofa new class of structurally rigid tricyclic chiral ligands based on thehexahydropyrrolo[2,3-b]indole skeleton which can be synthesized from anL-tryptophan derivative in four and five steps, respectively.

The invention is based on the identification of the tryptophan-basedhexahydropyrrolo[2,3-b]indole skeleton as a rigid backbone that iscapable for use to induce chirality. Two possible isomers, endo or exoisomer could be generated in the ring closure of tryptophan (Taniguchi,M, & Hino, T, Tetrahedron (1981) 37, 1487-1494; Bourne, G T, et al.,Perkin Trans. I (1991) 1693-1699; Crich, D, & Banerjee, A, Acc. Chem.Res. (2007) 40, 151-161). These two isomers upon complexes with metalwill result in rigid conformations: Bowl shaped conformation of FormulaVIII or S shaped conformation of Formula IX (shown in FIG. 6).

In one general aspect the invention relates to ahexahydropyrrolo[2,3-b]indole compound of general Formula (XX):

In this general Formula (XX) R may be —COOR³, —R⁴COOR³, —R⁴COSR³,R⁴COSeR³, —R⁴CHO, —COR³, —R⁴COR³, —R⁴CONR³R⁵, —R⁴COX, —R⁴OP(═O)(OH)₂,—R⁴P(═O)(OH)₂), —SO₂R³, —R⁴C(O)C(R³)CR⁵R⁶, —R⁴CO₂C(R³)O, aryl oraryl-methylenyl. R³¹ may be hydrogen, —COOR³, —R⁴COOR³, —R⁴COSR³,R⁴COSeR³, —R⁴CHO, —COR³, —R⁴COR³, —R⁴CONR³R⁵, —R⁴COX, —R⁴OP(═O)(OH)₂,—R⁴P(═O)(OH)₂), —SO₂R³, —R⁴C(O)C(R³)CR⁵R⁶ or —R⁴CO₂C(R³)O, i.e

as well as aryl or aryl-methylenyl. R³, R⁵ and R⁶ are independently fromone another hydrogen, or an aliphatic, an alicyclic, an aromatic, anarylaliphatic, or an arylalicyclic group that includes 0 to about 3heteroatoms independently selected from the group consisting of N, O, S,Se and Si. R⁴ is one of an aliphatic bridge, an alicyclic bridge, anaromatic bridge, an arylaliphatic bridge and an arylalicyclic bridge,comprising 0 to about 3 heteroatoms. The heteroatoms may again beindependently selected from N, O, S, Se and Si, Where R³, R⁴, R⁵ and/orR⁶ are an aliphatic moiety (including an aliphatic bridge), theytypically have a main chain that has one to about 20 carbon atoms,including about 2 to about 20 carbon atoms, about 1 to about 15 carbonatoms, about 2 to about 15 carbon atoms, about 2 to about 10 carbonatoms or about 1 to about 10 carbon atoms. X is a halogen or apseudohalogen.

In some embodiments R and/or R³¹ is/are a nitrogen protecting group, ofwhich numerous are known to those skilled in the art. In someembodiments R and R³¹ are identical. In some embodiments R and R³¹ aredifferent from each other. In some embodiments R³¹ is a nitrogenprotecting group that is removable, i.e. cleavable from the nitrogenatom, in the presence of hydrogen (H₂). Examples of nitrogen protectinggroups that are removed upon treatment with H₂ include, but are notlimited to, formyl, benzyl, p-methylbenzyl, p-ethylbenzyl,p-trifluoromethylbenzyl, p-methylbenzyl, 4-methoxybenzyl,9-phenylfluorenyl, diphenylmethyl, triphenylmethyl,phenylethoxycarbonyl, carbobenzyloxy (Cbz), p-dihydroxyboryl)benzyloxycarbonyl, benzisoxazolylmethoxy carbonyl. In some embodiments R is anitrogen protecting group that is stable in the presence of H₂. A lagenumber of such nitrogen protecting groups are availble. As a couple ofillustrative examples may serve methyl, tert-butyl, allyl, prenyl,methoxymethyl, 2,4-dinitrophenyl, p-methoxyphenyl, o-methoxyphenyl,fluorenyl, benzenesulfenyl, benzoyl, 4-toluenesulfonyl (Tosyl, Ts),methoxycarbonyl, ethoxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC),2,6-di-t-butyl-9-fluorenylmethyloxycarbonyl,2,7-bis(trimethylsilyl)fluorenylmethyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, trimethylsilylethoxycarbonyl,1,1-dimethyl-2,2-dibromoethoxycarbonyl,2-(N,N-dicyclohexylcarboxamidoethoxycarbonyl, tert-butyloxycarbonyl(BOC), p-methoxybenzyl carbonyl (Moz or MeOZ),1-(3,5-di-tert-butylphenyl)-1-methylethoxycarbonyl,triisopropylsiloxycarbonyl, vinyloxycarbonyl, prenyloxycarbonyl,p-methoxybenzyloxycarbonyl, methylsulfonylethylethoxy carbonyl,2-(p-toluenesulfonyl)ethoxy carbonyl, m-nitrophenyloxy carbonyl, to namea few.

R³⁰ in general Formula (XX) may be —C(OR¹¹)R¹²R¹³, —C(SR¹¹)R¹²R¹³,—C(SeR¹¹)R¹²R¹³, —COOR¹⁴, —COSR¹⁶, —COSeR¹⁶, —CON(R¹⁶)R¹⁷, —CN or —CHO.R¹¹ may be hydrogen, —OSO₂R¹⁵, —Si—R¹⁶R¹⁷R¹⁸ or an aliphatic, analicyclic, an aromatic, an arylaliphatic or an arylalicyclic group thatincludes 0 to about 3 heteroatoms independently selected from the groupconsisting of N, O, S, Se and Si. R¹² and R¹³ are independently from oneanother hydrogen, fluorine, —Si—R¹⁶R¹⁷R¹⁸ or an aliphatic, an alicyclic,an aromatic, an arylaliphatic, or an arylalicyclic group that includes 0to about 3 heteroatoms independently selected from the group consistingof N, O, S, Se and Si. R¹⁴ may be hydrogen, halogen, —Si—R¹⁶R¹⁷R¹⁸ or analiphatic, an alicyclic, an aromatic, an arylaliphatic or anarylalicyclic group that includes 0 to about 3 heteroatoms independentlyselected from the group consisting of N, O, S, Se and Si. As a furtherillustration, in some embodiments where R³⁰ is COOR¹⁴, R¹⁴ may be alkylor aryl-methylenyl. R¹⁵ may be an aliphatic, an alicyclic, an aromatic,an arylaliphatic or an arylalicyclic group that includes 0 to about 3heteroatoms independently selected from the group consisting of N, O, S,Se and Si. R¹⁶, R¹⁷ and R¹⁸ are independently from one another hydrogen,or an aliphatic, an alicyclic, an aromatic, an arylaliphatic, or anarylalicyclic group that includes 0 to about 3 heteroatoms independentlyselected from the group consisting of N, O, S, Se and Si. In someembodimentsone or more of R¹¹, R¹², R¹³, R¹⁴, R¹⁶, R¹⁷ and/or R¹⁸is/are, as applicable, identical to R. In some embodiments R¹¹, R¹²,R¹³, R¹⁴, R¹⁶, R¹⁷ and/or R¹⁸ is/are different from from R.

In some embodiments where R³⁰ is —COOR¹⁴, —COSR¹⁶, —COSeR¹⁶ or—CON(R¹⁶)R¹⁷, R¹⁴, R¹⁶ and R¹⁷ are independently hydrogen or aprotecting group that can be removed in the presence of the moiety R.Hence in some embodiments the bond between R and the correspondingnitrogen of the hexahydropyrrolo[2,3-b]indole sceleton is at leastessentially stable under conditions where R¹⁴, R¹⁶ and/or R¹⁷, as may beapplicable, are removable, including where these moieties are (/thismoity is), removed, In some embodiments R³⁰ is identical to R³¹. In someembodiments R¹⁴, R¹⁶ and R¹⁷ are different from R³¹. In some embodimentswhere R³⁰ is —COOR¹⁴, —COSR¹⁶, —COSeR¹⁶ or —CON(R¹⁶)R¹⁷, R¹⁴, R¹⁶ andR¹⁷ are independently hydrogen or a protecting group that can be removedunder conditions where R³¹ can be removed. Accordingly in someembodiments it is possible to simultaneously remove both R¹⁴, R¹⁶ andR¹⁷, as applicable, and R³¹ from a compound of general structure (XX)where R is a moiety that includes one or more of R¹⁴, R¹⁶ and R¹⁷, asdefined above.

In some embodiments R³¹ is removable upon contact with H₂, i.e. byhydrogenolysis. R³¹ may accordingly be a protecting group that iscleavable by means of exposure to H₂. Illustrative examples ofrespective moieties R³¹ are benzyl carbamoyl, trifluoroacetyl, benzyland triphenylmethyl (Trityl).

The term “aliphatic” means, unless otherwise stated, a straight orbranched hydrocarbon chain, which may be saturated, i.e. alkyl oralkylene, or mono- or poly-unsaturated and include heteroatoms (seeabove). An unsaturated aliphatic group contains one or more doubleand/or triple bonds (alkenyl or alkynyl moieties). The branches of thehydrocarbon chain may include linear chains as well as non-aromaticcyclic elements. The (main) chain of an aliphatic moiety (includingbridge), may, unless otherwise stated, be of any length, and contain anynumber of branches. Typically, the hydrocarbon (main) chain includes 1to about 5, to about 10, to about 15, to about 20, to about 30 or toabout 40 carbon atoms. Examples of alkenyl radicals are straight-chainor branched hydrocarbon radicals which contain one or more double bonds.Alkenyl radicals normally contain about two to about twenty carbon atomsand one or more, for instance two, double bonds, such as about two toabout ten carbon atoms, and one double bond. Alkynyl radicals normallycontain about two to about twenty carbon atoms and one or more, forexample two, triple bonds, such as two to ten carbon atoms, and onetriple bond. Examples of alkynyl radicals are straight-chain or branchedhydrocarbon radicals which contain one or more triple bonds. Examples ofalkyl groups are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,octyl, nonyl, decyl, the n isomers of these radicals, isopropyl,isobutyl, isopentyl, neopentyl, sec.-butyl, tert.-butyl, neopentyl and3,3-dimethylbutyl. Both the main chain as well as the branches mayfurthermore contain heteroatoms as for instance N, O, S, Se or Si orcarbon atoms may be replaced by these heteroatoms.

The term “alicyclic” may also be referred to as “cycloaliphatic” andmeans, unless stated otherwise, a non-aromatic cyclic moiety (e.g.hydrocarbon moiety), which may be saturated or mono-or poly-unsaturated.The cyclic hydrocarbon moiety may also include fused cyclic ring systemssuch as decalin and may also be substituted with non-aromatic cyclic aswell as chain elements. The main chain of the cyclic hydrocarbon moietymay, unless otherwise stated, be of any length and contain any number ofnon-aromatic cyclic and chain elements. Typically, the hydrocarbon(main) chain includes 3, 4, 5, 6, 7 or 8 main chain atoms in one cycle.Examples of such moieties include, but are not limited to, cyclopentyl,cyclohexyl, cycloheptyl, or cyclooctyl. Both the cyclic hydrocarbonmoiety and, if present, any cyclic and chain substituents mayfurthermore contain heteroatoms, as for instance N, O, S, Se or Si, or acarbon atom may be replaced by these heteroatoms. The term “alicyclic”also includes cycloalkenyl moieties that are unsaturated cyclichydrocarbons, which generally contain about three to about eight ringcarbon atoms, for example five or six ring carbon atoms. Cycloalkenylradicals typically have a double bond in the respective ring system.Cycloalkenyl radicals may in turn be substituted.

The term “aromatic” means an at least essentially planar cyclichydrocarbon moiety of conjugated double bonds, which may be a singlering or include multiple condensed (fused) or covalently linked rings,for example, 2, 3 or 4 fused rings. The term aromatic also includesalkylaryl. Typically, the hydrocarbon (main) chain includes 5, 6, 7 or 8main chain atoms in one cycle. Examples of such moieties include, butare not limited to, cyclopentadienyl, phenyl, napthalenyl-,[10]annulenyl-(1,3,5,7,9-cyclodecapentaenyl-), [12]annulenyl-,[8]annulenyl-, phenalene (perinaphthene), 1,9-dihydropyrene, chrysene(1,2-benzophenanthrene). An example of an alkylaryl moiety is benzyl.The main chain of the cyclic hydrocarbon moiety may, unless otherwisestated, be of any length and contain any number of heteroatoms, as forinstance N, O and S. Such a heteroaromatic moietie may for example be a5- to 7-membered unsaturated heterocycle which has one or moreheteroatoms from the series O, N, S. Examples of such heteroaromaticmoieties (which are known to the person skilled in the art) include, butare not limited to, furanyl-, thiophenyl-, naphtyl-, naphthofuranyl-,anthrathiophenyl-, pyridinyl-, pyrrolyl-, quinolinyl,naphthoquinolinyl-, quinoxalinyl-, indolyl-, benzindolyl-, imidazolyl-,oxazolyl-, oxoninyl-, oxepinyl-, benzoxepinyl-, azepinyl-, thiepinyl-,selenepinyl-, thioninyl-, azecinyl-, (azacyclodecapentaenyl-),diazecinyl-, azacyclododeca-1,3,5,7,9,11-hexaene-5,9-diyl-, azozinyl-,diazocinyl-, benzazocinyl-, azecinyl-, azaundecinyl-,thia[11]annulenyl-, oxacyclotrideca-2,4,6,8,10,12-hexaenyl- ortriazaanthracenyl-moieties.

By the term “arylaliphatic” is meant a hydrocarbon moiety, in which oneor more aromatic moieties are substituted with one or more aliphaticgroups. Thus the term “arylaliphatic” also includes hydrocarbonmoieties, in which two or more aryl groups are connected via one or morealiphatic chain or chains of any length, for instance a methylene group.In this regard, the term “aryl-methylenyl” includes the moieties —CH₂ar,—CHar₂ and —Car₃, with ‘ar’ representing an aromatic moiety. The twoaromatic moieties in embodiment —CHar₂ and the three aromatic moietiesin embodiment —Car₃ may be identical or different. The term“aryl-methylenyl” also includes the moiety —CH(alkyl)ar, with alkylrepresenting a cyclic or straight alkyl chain of 1 to about 10, 1 toabout 8 or 1 to about 6 main chain atoms, including methyl, ethyl,propyl, isopryl, n-butyl or isobutyl. Typically, the hydrocarbon (main)chain of an arylaliphatic compound includes 5, 6, 7 or 8 main chainatoms in each ring of the aromatic moiety. Examples of arylaliphaticmoieties include, but are not limited, to 1-ethyl-naphthalene,1,1′-methylenebis-benzene, 9-isopropylanthracene,1,2,3-trimethyl-benzene, 4-phenyl-2-buten-1-ol,7-chloro-3-(1-methylethyl)-quinoline, 3-heptyl-furan,6-[2-(2,5-diethylphenyl)ethyl]-4-ethyl-quinazoline or7,8-dibutyl-5,6-diethyl-isoquinoline.

As already indicated above, each of the terms “aliphatic”, “alicyclic”,“aromatic” and “arylaliphatic” as used herein is meant to include bothsubstituted and unsubstituted forms of the respective moiety.Substituents may be any functional group such as —COOH (carboxy), —OH(hydroxy), —SH (thiol-), a dithiane-, —SeH (seleno-), —CHO (aldehyde),—CO— (carbonyl), —S(O₂)— (sulfonyl), sulfo-, sulfido-, —O— (oxo),sulfate (—OSO₃H), —NH₂ (amino), —NO (nitro), —NS, —NSe, a halogen suchas —Br (bromo), —Cl (chloro) or —F (fluoro), an amino-, an imino-, anamido-, an imido-, an azido-, a diazo-, a cyano-, an isocyano-, athiocyano-, a nitro-, a nitroso-, a sulfonyl- (e.g. a trifluoromethylsulfonyl-, p-toluenesulfonyl-, bromobenzenesulfonyl-,nitrobenzenesulfonyl-, or a methane-sulfonyl), silyl-, silano- or asiloxy-group.

In some embodiments where R³⁰ is COOR¹⁴, a compound of general Formula(XX) can be represented by Formula (XXI)

In Formula (XXI) R and R³¹ are as defined above. R³⁵ is one of hydrogen,alkyl and a protecting group that is removable in the presence of of themoiety R. An example of such a protecting group is arylmethylenyl. Asalready explained above, in some embodiments R³⁵ is identical to R,while in other embodiments R³⁵ is different from from R. In someembodiments R³⁵ is a protecting group that can be removed in thepresence of the moiety R. Thus in some embodiments the ester bondbetween R³⁵ and the carboxyl group can be cleaved under conditions wherethe bond between R and the nitrogen of the hexahydropyrrolo[2,3-b]indolesceleton is left at least essentially intact. In some embodiments R³⁵ isidentical to R³¹. In some embodiments R³⁵ is different from from R³¹. Insome embodiments R³⁵ is a protecting group that can be removed underconditions where R³¹ can be removed. Accordingly in some embodiments itis possible to simultaneously remove both R³⁵ and R³¹ from a compound ofgeneral structure (XX).

In the Formulas depicting hexahydropyrrolo[2,3-b]indole compounds asused herein, the well established wedge representation is used to definethe stereochemical configuration of the tricyclic moieties. The wedgerepresentation defines one orientation of a substituent relative toanother substituent and relative to a ring structure (see e.g. Pine,Hendrickson, Cram, Hammond: Organic Chemistry, McGraw-Hill, 4th edition,1981, pages 97-99 & 115-119). By defining nonsuperimposable mirrorimages the absolute stereochemistry can accordingly be derived from therespective wedge representation.

The stereochemistry of the respective compound may be analysed accordingto any method known in the art, such as for instance 2D-NMR based onhomo- or heteronuclear J-coupling values (Riccio, R., et al., Pure Appl.Chem. (2003) 75, 2-3, 295-308), electron ionisation mass spectrometry,polarimetry, circular dichroism spectroscopy (e.g. using the splitCotton-effect based on the Davydov splitting, see e.g. Allemark, S. G.,Nat. Prod. Rep. (2000) 17, 145-155), enantioselective chromatography,derivatization in combination with standard analytical techniques suchas NMR, including any suitable 2D-NMR technique, for example based onthe nuclear Overhauser effect, as well as X-ray crystallography or solidstate NMR (see e.g. Harper, J. K., et al., J. Org. Chem. (2003) 68,4609-4614).

In embodiments where R³¹ is hydrogen, a respective compound may also berepresented by Formula (XXIA)

In Formula (XXIA) R and R³⁵ are as defined above.

Accordingly, in other embodiments a compound of Formula (XXI) can berepresented by Formula (XXIB)

In Formula (XXIB) R and R³⁵ are as defined above. Y is a nitrogenprotecting group. In some embodiments Y is removable upon contact withH₂, i.e. by hydrogenolysis. Examples of a suitable nitrogen protectinggroup include, but are not limited to, a carbamate, methyl, t-butyl,N-allyl, benzyl, N-4-methoxybenzyl, N-2,4-dimethoxybenzyl,N-2-hydroxybenzyl, N-prenyl, N-cinnamyl, N-2-phenylallyl, N-propargyl,methoxymethyl, N-([2-(Trimethylsilyl)ethoxy]methyl, N-3-Acetoxypropyl,N-cyanomethyl, an N-2-Azanorborne, N-2,4-dinitrophenyl,N-p-methoxyphenyl, N-o-methoxyphenyl, N-Ifluorenyl, N-9-phenylfluorenyl,an amide or an aminocarbonyl group of a general underlying structurethat corresponds to urea (cf. also above for further examples).Illustrative examples of carbamates are methyl-carbamate,ethylcarbamate, t-butyl carbamate, t-amyl carbamate, vinylcarbamate,allyl carbamate, triisopropylsiloxy carbamate, 4-nitrocinnamylcarbamate, 9-Fluorenylmethyl carbamate (Fmoc),2,6-dibutyl-9-Fluorenylmethyl carbamate (Dtb-Fmoc),2,7-bis(trimethylsilyl)fluorenylmethyl carbamate (Bts-Fmoc),17-tetrabenzo[a,c,g,i]-fluorenylmethyl carbamate,9-(2-sulfo)fluorenylmethyl carbamate, 2-chloro-3-indenyl-methylcarbamate (Climoc), benz[f]inden-3-ylmethyl carbamate (Bimoc),9-(2,7-dibromo)-fluorenylmethyl carbamate,1,1-dioxobenzyo[b]thiophene-2-ylmethyl carbamate (Bsmoc),2-methylsulfonyl-3-phenyl-1-prop-2-enyloxy carbamate (Mspoc),2,7-di-t-butyl[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 2,2,2-trichloroethyl carbamate (Troc),2-trimethylsilyl carbamate (Teoc), (2-phenyl-2-trimethylsilyl)ethylcarbamate (Psoc), 2-phenylethyl carbamate, 2-chloroethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate,1,1-dimethyl-2,2,2-trichloroethyl carbamate, 2-(2′-pyridyl)ethylcarbamate, 2-(4′-pyridyl)ethyl carbamate, 2,2-bis(4′-nitrophenyl)ethylcarbamate, 2-[(2-nitrophenyl)dithio]-1-phenylethyl carbamate,2-(N,N′-dicyclohexylcarboxamido)ethyl carbamate, 1-adamantyl carbamate,1-(1-adamantyl)-1-methyl carbamate, 1-methyl-1-(4-biphenyl-yl)ethylcarbamate, 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate,8-quiolylcarbamate, N-hydroxypiperidinyl carbamate, an alkyldithiocarbamate (in particular with alkyl being methyl, ethyl, isopropyl,n-propyl or t-butyl), phenyldithio carbamate, 3,5-di-t-butylbenzylcarbamate, p-methoxybenzyl carbamate, p-nitrobenzyl carbamate, ahalobenzyl carbamate, 2-naphtylmethyl carbamate, diphenylmethylcarbamate, 9-anthrylmethyl carbamate, 4-phenylacetoxy carbamate,4-azidobenzyl carbamate, 2-methylthioethyl carbamate,2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate,[2-(1,3-dithiany)-methyl carbamate,1,1-dimethyl-2-cyanoethyl carbamate,2-(4-nitrophenyl)ethyl carbamate, m-nitrophenyl carbamate,3,5-dimethoxybenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate and4-methoxyphenacyl carbamate. Illustrative examples of suitable amidesare formamide, acetamide, chloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, pent-4-enamide, picolinamide,3-pyridylcarboxacetamide, benzamide, p-phenylbenzamide,o-(benzyloxymethyl)benzamide, o-hydroxy-trans-cinnamide,2-([t-butyl-diphenylsiloxy]methyl]benzoyl, o-hydroxy-trans-cinnamide,4-chlorobutanamide, aceto-acetamide and2-methyl-2-(o-phenylazophenoxy)propanamide. Illustrative examples ofsuitable aminocarbonyl groups of a general underlying structure thatcorresponds to urea are the phenothiazinyl-(10)-carbonyl group, theN′-p-tuloenesulfonylaminocarbonyl group, the N′-phenylaminothiocarbonylgroup, the 4-hydroxyphenylaminocarbonyl group and the3-hydroxytryptaminocarbonyl group. Further suitable examples of anitrogen protecting group include, but are not limited to, sulfonylgroups such as methanesulfonyl, trifluoromethanesulfonyl,t-butylmethanesulfonyl, benzylsulfonyl, 2-(trimthylsilyl)ethanesulfonyl,p-toluenesulfonyl, o-anisylsulfonyl, dinitrobenzenesulfonyl ornaphtalenesulphonyl. Yet further suitable examples of a nitrogenprotecting group include, but are not limited to, silyl groups such ast-butyldiphenylsilyl, sulfenyl groups such as benzenesulfenyl,2,4-dinitrobenzenesulfenyl, pentachlorobenzenesulfenyl,triphenylmethylsulfenyl or 3-nitro-2-pyridinesulfenyl.

In some embodiments R³⁰ in general Formula (XX) is —C(R¹)(R²)OH.Typically, in such embodiments Y in general Formula (XX) is hydrogen. Insome embodiments a respective hexahydropyrrolo[2,3-b]indole compound canbe represented by Formula (VII):

In Formula (VII) R is one of of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³,—R⁴CONR⁵R⁶, —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂), —R⁴C(O)C(R³)CR⁵R⁶and —R⁴CO₂C(R³)O. R³, R⁵ and R⁶ are independent from one another one ofhydrogen, an aliphatic group, an alicyclic group, an aromatic group, anarylaliphatic group and an arylalicyclic group, that includes 0 to about3 heteroatoms, such as one, two or three heteroatoms. Examples ofsuitable heteroatoms, i.e. atoms different from carbon, include, but arenot limited to, N, O, S, Se and Si. R⁴ is one of an aliphatic bridge, analicyclic bridge, an aromatic bridge, an arylaliphatic bridge and anarylalicyclic bridge, that includes 0 to about 3 heteroatoms, such as N,O, S, Se and Si, In a compound of Formula (VII) an aliphatic group(including an aliphatic bridge) typically has a main chain that has 1 toabout 20 carbon atoms, such as 1 to about 15, 1 to about 12, or 1 toabout 10 carbon atoms, including about 2 to about 20 carbon atoms, about2 to about 15 carbon atoms, 1 about 2 to about 12 or about 2 to about 10carbon atoms. Accordingly, in some embodiments a corresponding aliphaticgroup is (C₁-C₁₀) alkyl. As indicated above, the aliphatic group may inaddition have up to three heteroatoms. As explained above, aliphaticgroups may be alkyl radicals, which may be substituted by one or moresubstituents, such as by —OH, —O—(C₁-C₁₀)-alkyl, —O-phenyl,—O—CO—(C₁-C₁₀)-alkyl, —O—CO-aryl, —CO—(C₁-C₅)-alkyl,—CO—O—(C₁-C₅)-alkyl, —CO—O-aryl, or aryl. Likewise, an alicyclic group,an aromatic group, an arylaliphatic group and an arylalicyclic group maybe substituted by one or more identical or different substituents. Thesemay for instance be selected from from the group of halogen,(C₁-C₅)-alkyl or phenyl, —OH, —O—(C₁-C₅)-alkyl, (C₁-C₂)-alkylenedioxy,—NO₂, —CO—(C₁-C₅)-alkyl, —CF₃, —CN, —CONR⁷R⁸, —COOH,—CO—O—(C₁-C₅)-alkyl, —(C₁-C₅)-alkyl, where R⁷ and R⁸ are independentfrom one another one of hydrogen, an aliphatic group, an alicyclicgroup, an aromatic group, an arylaliphatic group and an arylalicyclicgroup, that includes 0 to about 3 heteroatoms, such as one, two or threeheteroatoms. In some embodiments an alicyclic, an aromatic, anarylaliphatic or an arylalicyclic group (including a respective bridge)representing one of R³, R⁴, R⁵ and R⁶ may likewise have a main chainthat has 1 to about 20, such as 1 to about 15, 1 to about 12, or 1 toabout 10 carbon atoms, including about 2 to about 20 carbon atoms, about2 to about 15 carbon atoms, 1about 2 to about 12 or about 2 to about 10carbon atoms. In some embodiments a corresponding alicyclic group is(C₃-C₈) cycloalkyl, such as a four-membered, a five-membered, asix-membered a seven-membered or an eigth-membered alicyclic ring. Insome embodiments some or all of R³, R⁴, R⁵ and R⁶, as present in acorresponding compound, are identical. X is a halogen atom, such as F,Cl, Br, or I.

R¹ and R² are independent from each another selected from hydrogen, analiphatic group, an alicyclic group, an aromatic group, an arylaliphaticgroup and an arylalicyclic group. The above said for an aliphatic groupand embodiments of an alicyclic, an aromatic, an arylaliphatic or anarylalicyclic group, also applies to R¹ and R². In some embodiments R¹and R² are identical, whereas in other embodiments they are different.In one such embodiment R¹ and R² are both aryl. As noted above, aryl maybe phenyl, naphthyl, or alkylaryl, for example, tolyl, xylyl, orheteroaryl, all of which may be substituted by one or more identical ordifferent substituents selected from from the group halogen,(C₁-C₅)-alkyl or phenyl, —OH, —O—(C₁-C₅)-alkyl, (C₁-C₂)-alkylenedioxy,—NO₂, —CO—(C₁-C₅)-alkyl, —CF₃, —CN, —CONR⁷R⁸, —COOH,—CO—O—(C₁-C₅)-alkyl, —(C₁-C₅)-alkyl. R⁷ and

R⁸ are independent from one another one of hydrogen, an aliphatic groupwith a main chain having 1 to about 20 carbon atoms, an alicyclic group,an aromatic group, an arylaliphatic group and an arylalicyclic group,comprising 0 to about 3 heteroatoms independently selected from thegroup consisting of N, O, S, Se and Si. As also explained above,aliphatic groups may be alkyl radicals, which may be substituted by oneor more substituents, such as by —OH, —O—(C₁-C₁₀)-alkyl, —O-phenyl,—O—CO—(C₁-C₁₀)-alkyl, —O—CO-aryl, —CO—(C₁-C₅)-alkyl,—CO—O—(C₁-0₅)-alkyl, —CO—O-aryl, or aryl.

In some embodiments a respective a hexahydropyrrolo[2,3-b]indolecompound is provided in form of a compound of Formula (VIII)

As can be taken from Formula (VIII), the compound has a bowl-shapedconformation. In Formula (VIII) M is a metal compound selected from thegroup consisting of Group 1 to Group 14 metals of the periodic table ofthe chemical elements (according to the new IUPAC system), lanthanidesand actinides. In some embodiments M may for instance be a compound of ametal of Group 13, such as a boron compound, including an organo boranecompound, an aluminium compound, including an aluminium organiccompound, an indium compound, including an indium organic compound, or agallium compound, including a gallium organic compound. In someembodiments M may for instance be a compound of a metal of Group 13,such as Zinc compound. In some embodiments M may be a compound of ametal of Group 14, such as tin compound. In some embodiments M may be acompound of a metal of Group 12, such as a zinc compound or a cadmiumcompound. In some embodiments M may be a compound of a metal of Group11, such as a copper or a silver compound. In some embodiments M may bea compound of a metal of Group 9, such as an iridium compound or arhodium compound. In some embodiments M may be a compound of a metal ofGroup 4, such as a titanium compound or a zirconium compound. In someembodiments M may be a compound of a lanthanide such as lanthanum orcerium. As a few illustrative examples, M may in some embodiments be oneof BH₃, B₂H₆, B₅H₉, B₁₀H₁₄, AlCl₃, ZnCl₂, Zn(OTf)₂, ZnEt₂, SnCl₂, TiCl₄,Ti(Oi-Pr)₄, Cp₂TiCl₂, ZrCl₄, Cp₂ZrCl₂, InCl₃, In(OTf)₃, Cu(OAc)₂,(IrCp*Cl₂)₂, (Ir(COD)Cl)₂, LnCl₃, and LnCp₂Cl₂. R, R¹ and R² are asdefined above.

In some embodiments a respective hexahydropyrrolo[2,3-b]indole compoundhas an S-shaped conformation and can be represented by Formula (IX)

In Formula (IX) moieties M, R, R¹ and R² are as defined above.

In some embodiments R³⁰ in general Formula (XX) is —COOR⁹ or —COOR¹⁰. Insome of these embodiments a respective hexahydropyrrolo[2,3-b]indolecompound can be represented by Formula (VI)

In Formula (VI) R⁹ is an aliphatic moiety, which may in some embodimentshave a main chain that includes 1 to about 20 carbon atoms, such as suchas 1 to about 15, 1 to about 12, or 1 to about 10 carbon atoms.Acordingly, in some embodiments a corresponding aliphatic group is(C₁-C₁₀) alkyl. As indicated above, the aliphatic group may in additionhave up to three heteroatoms. In some embodiments, R⁹ is one of methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl ortrifluoromethyl. In some embodiments R and R⁹ are identical.

In some of these embodiments a respective hexahydropyrrolo[2,3-b]indolecompound can be represented by Formula (IV)

In Formula (IV) Y is a nitrogen protecting group (cf. above). Y may insome embodiments be sensitive to H₂, i.e. removable by hydrogenolysis.In one embodiment, the nitrogen protecting group is selected from thegroup consisiting of alkoxycarbonyl, benzyhdryl, trifluoroacetyl group,t-butoxycarbonyl group, carbamates including methyl, ethyl andsubstituted ethyl carbamates, amides, cyclic imide derivatives, N-Alkyland N-Aryl amines, imine derivatives, and enamine derivatives. R and R⁹are as defined above.

In further embodiments a respective hexahydropyrrolo[2,3-b]indolecompound can be represented by Formula (IVA)

In Formula (IVA) R¹⁰ is a protecting group that is removable in thepresence of of the moiety R. An example of such a protecting group isarylmethylenyl. Examples of suitable aryl-methylenyl groups include, butare not limited to, benzyl, diphenylmethyl, dibenzysuberyl,2,4,6-trimethylbenzyl, p-bronobenzyl, o-nitrobenzyl, p-nitrobenzyl,4-sulfobenzyl, 4-picolyl, 2-naphthylmethyl and1,2,3,4-tetrahydro-1-naphthyl. As already explained above, in someembodiments R¹⁰ is a protecting group that can be removed in thepresence of the moiety R. Thus in some embodiments the ester bondbetween R¹⁰ and the carboxyl group can be cleaved under conditions wherethe bond between R and the nitrogen of the hexahydropyrrolo[2,3-b]indolesceleton is left at least essentially or entirely intact. In someembodiments R¹⁰ is a protecting group that can be removed underconditions where Y can be removed. Accordingly in some embodiments it ispossible to simultaneously remove both Y and R¹⁰ from a compound ofgeneral structure (IVA). An example of conditions where this isachievable is an embodiment where R¹⁰ is arylmethylenyl and its removalis carried out via hydrogenolysis. R and Y are as defined above.ln someembodiments Y may be removable by hydrogenolysis.

In further embodiments a respective hexahydropyrrolo[2,3-b]indolecompound can be represented by Formula (VIA)

In Formula (VIA) R is as defined above.

Compounds according to the invention of the Formula (VII) can beobtained as shown in FIG. 15. Starting from the commercially availableNα-protected L-tryptophan 1, for example Na-carbobenzyloxy-L-tryptophan,initial DCC coupling with methanol followed by acid catalyzed ringclosure provided the hexahydro[2,3-b]pyrrolo indole 3 asdiastereoisomeric cyclic tautomers. In agreement with literatureprecedent (Taniguchi, M, & Hino, T, Tetrahedron (1981) 37, 1487-1494;Bourne, G T., et al., J. Chem. Soc., Perkin Trans. I (1991) 1693-1699;Crich, D, & Banerjee, A, Acc. Chem. Res. (2007) 40, 151-161), aftersodium carbonate-mediated protection, the thermodynamically stable transisomer of compound (IV) was obtained and the less stable diastereoisomerreverted back to starting material 1. Initial attempts to directGrignard addition to compound (IV) (cf. FIG. 2) were, surprisingly,unsuccessful. No reaction was observed. It was speculated that thiseffect might be caused by the highly crowded nature of the structure. Toremove the steric effect, an alternative approach was followedbyremoving the protecting group first, followed by subsequent Grignardaddition. This strategy proved successful and a series of chiral ligands7a-h were obtained in good yields (FIG. 15).

Thus the present invention provides a method of preparing a compound ofFormula (VII)

by reacting a compound of Formula (VI)

with a Grignard reagent R¹MgX , R²MgX or a mixture of R¹MgX and R²MgX.R¹ and R² in the Grignard reagent and in Formula (VI) are as definedabove. R in Formulas (VII) and (VI) and Y in Formula (VI) are also asdefined above. Generally, Y is removable upon contact with H₂, i.e. byhydrogenolysis.

The present invention further provides a method of forming a compound ofFormula (XXIA)

in which R and R³⁵ are as defined above. R³¹ of Formula (XXI) ishydrogen. The method includes providing a compound of Formula (XXIB)

In Formula (XXIB) R and R³⁵ are as defined above. Y is a nitrogenprotecting group (supra), which is generally removable upon contact withH₂, i.e. by hydrogenolysis. The method further includes contacting thecompound of Formula (XXIB) with H₂ in the presence of a suitablecatalyst such as a heterogeneous catalyst. Typical examples of aheterogeneous catalyst are a Raney catalyst (e.g. Raney nickel), Adam'scatalyst, Palladium black or a carrier based catalst such as a Pd/C,Ni/C, Rh/C or a Lindlar catalyst, Palladium Black, or Raney nickel.Thereby cleavage of the bond between moiety Y and the correspondingnitrogen atom of the tricyclic compound of Formula (XXIB) is allowed tooccur. Accordingly, deprotection of the Na group of the compound ofFormula (XXIB) is allowed. Where R³⁵ is arylmethylenyl such as benzyl acleavage of the ester bond to moiety R³⁵ is in the same processeffected. Thus deprotection of the carboxyl group of the tricycliccompound of Formula (XXIB) is allowed to occur in such embodiments.

Deprotection of the Na group of the compound of Formula (XXIB) may beallowed to occur in any desird solvent, whether nonpolar (aprotic),dipolar protic or dipolar aprotic. Typically an organic solvent is used.Examples of non-polar solvents include, but are not limited to, hexane,heptane, cyclohexane, benzene, toluene, pyridine, dichloromethane,1,2-dichloroethane, chloroform, carbon tetrachloride, carbon disulfide,tetrahydrofuran, dioxane, diethyl ether or diisopropylether. Examples ofdipolar aprotic liquids are methyl ethyl ketone, chloroform,tetrahydrofuran, dioxane, ethylene glycol monobutyl ether, pyridine,methyl isobutyl ketone, acetone, cyclohexanone, ethyl acetate, isobutylisobutyrate, ethylene glycol diacetate, dimethylformamide, acetonitrile,N,N-dimethyl acetamide, nitromethane, acetonitrile, N-methylpyrrolidone,methanol, ethanol, propanol, isopropanol, butanol,N,N-diisopropylethylamine, and dimethylsulfoxide. In some embodimentsallowing deprotection of the Nα group of the compound of Formula (XXIB)and thus of the formation of a compound of Formula (XXIA) is carried outin a polar protic solvent. Examples of polar protic solvents include,but are not limited to methanol, ethanol, butyl alcohol, formic acid,dimethylarsinic acid [(CH₃)₂AsO(OH)], N,N-dimethyl-formamide,N,N-diisopropylethylamine, or chlorophenol.

In some embodiments the method of forming a compound of Formula (XXIA)is a method of forming a compound of Formula (VI) according to thepresent invention (see above)

The method includes providing a compound of Formula (IV) as definedabove

The method further includes contacting the compound of Formula (IV) withH₂ in the presence of a Pd/C catalyst, a Ni/C catalyst, a Rh/C catalystor another suitable catalyst as illustrated above. Thereby cleavage ofthe bond between moiety Y and the corresponding nitrogen atom of thetricyclic compound of Formula (IV) is allowed to occur. Hence, themethod includes allowing the Nα group of the compound of Formula (IV) tobe deprotected in the presence of Pd/C catalyst.

In some embodiments providing the compound of Formula (IV) includesproviding a compound of Formula (III)

In Formula (III) R⁹ is alkyl as defined above. In some embodiments, R⁹is (C₁-C₁₀) alkyl, such as methyl, ethyl, propyl, or butyl. Y is anitrogen protecting group as explained above. In one embodiment, thenitrogen protecting group is selected from alkoxycarbonyl, benzhydryl,the trifluoroacetyl group, the t-butoxycarbonyl group, a carbamateincluding methyl-, ethyl- and substituted ethyl carbamates, an amide, acyclic imide derivative, an N-Alkyl amine, an N-Aryl amine, an iminederivative, and an enamine derivative. The compound of Formula (III) iscontacted with an acyl halide RCOX in the presence of an inorganic basesuch as an alkali base. The inorganic base typically has an alkalimetal, alkali earth metal, or other metallic cation, and an anion suchas hydroxide, carbonate or bicarbonate. Examples of a suitable inorganicbase include, but are not limited to, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogen carbonate sodiumhydroxide, potassium hydroxide and calcium carbonate. In Formula RCOXmoiety X is halogen such as F, CI, Br or I. R is as defined above.

Contacting the compound of Formula (III) with an acyl halide RCOX may becarried out in any desired solvent in which the acyl halide is stable ton extent that the desired reaction can proceed. Accordingly, typicallyan organic solvent is used. In some embodiments contacting the compoundof Formula (III) with an acyl halide RCOX is carried out in a dipolarprotic solvent. Examples of dipolar aprotic solvents include, but arenot limited to, methyl ethyl ketone, chloroform, tetrahydrofuran,dioxane, ethylene glycol monobutyl ether, pyridine, methyl isobutylketone, acetone, cyclohexanone, ethyl acetate, isobutyl isobutyrate,ethylene glycol diacetate, dimethylformamide, acetonitrile, N,N-dimethylacetamide, nitromethane, acetonitrile, N-methylpyrrolidone, methanol,ethanol, propanol, isopropanol, butanol, N,N-diisopropylethylamine, anddimethylsulfoxide.

In related embodiments of forming a compound of Formula (XXIA) (supra)according to the invention a compound of Formula (VIA), as definedabove, is synthesized.

In Formula (VIA) R is as defined above.

The respective method (or embodiment with regard to forming a compoundof Formula (XXIA)) includes providing a compound of Formula (IVA) asdefined above

The method further includes contacting the compound of Formula (IVA)with H₂ in the presence of a Pd/C catalyst. Thereby cleavage of the bondbetween moiety Y and the corresponding nitrogen atom of the tricycliccompound of Formula (IV) is allowed to occur. Hence, the method includesallowing the Na group of the compound of Formula (IV) to be deprotectedin the presence of Pd/C catalyst. Further the cleavage of the ester bondbetween moiety R¹⁰ and the corresponding carbonyl group is allowed tooccur.

In some embodiments providing the compound of Formula (IV) includesproviding a compound of Formula (IIIA) as defined above

The compound of Formula (IIIA) is contacted with an acyl halide RCOX inthe presence of an inorganic base such as an alkali base. Examples of asuitable inorganic base include, but are not limited to, sodiumcarbonate, potassium carbonate, sodium hydroxide, potassium hydroxideand calcium carbonate. In Formula RCOX moiety X is halogen such as F,Cl, Br or I, and R is as defined above. In some embodiments contactingthe compound of Formula (IIIA) with an acyl halide RCOX is carried outin a dipolar protic solvent (supra).

A compound of Formula (VI) as defined above is used in a further methodaccording to the invention. The respective method is a method of forminga compound of Formula (VIII) as defined above

The method includes providing a compound of Formula (VI), for instanceby forming the same as defined above, or by obtaining the same inanother way. The compound of Formula (VI)

is contacted with a compound R¹MgX, R²MgX or a mixture of R¹MgX andR²MgX. R¹ and R² are as defined above and X is halogen (supra). As notedabove, in some embodiments R¹ and R² are identical, in which case onlyone compound R¹MgX or R²MgX needs to be contacted with the compound ofFormula (VI). In some embodiments contacting the compound of Formula(VI) with a compound R¹MgX, R²MgX or a mixture thereof is carried out ina dipolar protic solvent (supra).

Further, a method of forming a compound of Formula (IV) as defined aboveis provided

The method includes providing a compound of Formula (III) as definedabove

The compound of Formula (III) is contacted with an acyl halide RCOX(supra) in the presence of an inorganic base as defined above. In someembodiments contacting the compound of Formula (III) with an acyl halideRCOX is carried out in a dipolar protic solvent (supra).

In a related method the invention provides a method of forming acompound of Formula (IVA) as defined above

The method includes providing a compound of Formula (IIIA) as definedabove

The compound of Formula (IIIA) is contacted with an acyl halide RCOX(supra) in the presence of an inorganic base as defined above. In someembodiments contacting the compound of Formula (IIIA) with an acylhalide RCOX is carried out in a dipolar protic solvent (supra).

The present invention also provides a method of forming a compound ofFormula (VIII) as defined above

The method includes providing a compound of Formula (VII) as definedabove, for instance by forming the same as defined above, or byobtaining the same in another way. The compound of Formula (VII)

is contacted with a metal compound selected from the group consisting ofGroup 1 to Group 14 metals, lanthanides and actinides. In one embodimentof the invention, the metal compound M is selected from the groupconsisting of BH₃, B₂H₆, B₅H₉, B₁₀H₁₄, AlCl₃, ZnCl₂, Zn(OTf)₂, ZnEt₂,SnCl₂, TiCl₄, Ti(Oi-Pr)₄, Cp₂TiCl₂, ZrCl₄, Cp₂ZrCl₂, InCl₃, In(OTf)₃,Cu(OAc)₂, (IrCp*Cl₂)₂, (Ir(COD)Cl)₂, LnCl₃, LnCp₂Cl₂.

The present invention also provides a method of preparing a compound ofFormula (IX) as defined above

The method includes providing a compound of Formula (VII) as definedabove, for instance by forming the same as defined above, or byobtaining the same in another way. The compound of Formula (VII)

is contacted with a metal compound selected from the group consisting ofGroup 1 to Group 14 metals, lanthanides and actinides, (see above).

As explained above, in one embodiment, the metal compound M can beselected from the group consisting of BH₃, B₂H₆, B₅H₉, B₁₀H₁₄, AlCl₃,ZnCl₂, Zn(OTf)₂, ZnEt₂, SnCl₂, TiCl₄, Ti(Oi-Pr)₄, Cp₂TiCl₂, ZrCl₄,Cp₂ZrCl₂, InCl₃, In(OTf)₃, Cu(OAc)₂, (IrCp*Cl₂)₂, (Ir(COD)Cl)₂, LnCl₃,and LnCp₂Cl₂. It is noted that a compound of Formula (IX) is often notstable under acidic conditions. However, using a radical reagent such asN-phenylselenophtalimide in an aprotic nonpolar solvent in the presenceof pyridinium p-toluenesulfonate such difficulties may be avoided (cf.e.g Depew, K M, et al., J. Am. Chem. Soc. (1999) 1221, 11953-11963).

The present invention also relates to the use of the compounds ofFormula VII as chiral ligand for asymmetric catalysis, particularly tothe asymmetric reduction of ketones. In these uses the respectivecompound serves as a so called “active catalyst” in that it converts anachiral reactant to a chiral product. Such a chiral product hasasymmetry, in that it is non-superposable on its mirror image. Withoutthe intent of being bound by theory it is believed that the tricylicrigid ring system of the hexahydropyrrolo-[2,3-b]indole skeletonprovides a chiral pocket that directs the stereochemistry of reactionscatalysed by a respective compound. Hence, the chiral moiety has amirror image, which would provide the chiral chromatography stationaryphase with identical physical properties in non-chiral environments. Asillustrated in e.g. FIG. 5 or FIG. 8 the invention thereby provides avariety of methods of stereoselective synthesis.

The use of these chiral ligands for asymmetric catalysis is for exampleillustrated in the asymmetric reduction of ketones as shown in theexamples below (see also FIGS. 11 and 12). Such a use includes theformation of enantiomerically enriched, including at least essentiallyenantiomerically pure, secondary alcohols. The term “at leastessentially enantiomerically pure” refers to an enantiomeric excess(e.e.) of at least 95%, such as an excess (e.e.) of at least 96%, atleast 97%, at least 98% or at least 99%, including an e.e. of more than99.5%. As an illustrative example, a sample with 98.5% of R isomer and1.5% of S isomer has an enantiomeric excess of 97%. Accordingly, such amixture can also be taken as a mixture of 97% pure R isomer with 3% of aracemic mixture. In the exemplay scheme on top of FIG. 11, R²³ and R³³are independently from one another an aliphatic, an alicyclic, anaromatic, an arylaliphatic, or an arylalicyclic group that includes 0 toabout 3 heteroatoms independently selected from the group consisting ofN, O, S, Se and Si. Any reducing agent such as a borane, a silane, or ahydride such as tetrahydridoborate or tetrahydridoaluminate may be used,with which a compound of Formula (VII) may be employed as a ligand.

The asymmetric Michael reaction is recognized as a highly importantenantioselective carbon-carbon bond-forming reaction. Accordingly, thesuitability of the compounds of Formula (VIA) of the invention has beenexamined. The data summarized in FIG. 13 and FIG. 14 illustrate thesuitability of the catalysts to be used in a variety of solvents. Insome embodiments a basic cocatalyst is used together with the compoundof Formula In some embodiments the basic cocatalyst is an organiccompound such as an amine, for example an amine such as ethylamine,triethylamine, n-butylamine, di-n-butylamine, piperidine,isopropylamine, dimethylamine, cyclohexylamine, dicyclohexylaminepyridine, methylpyridine, dimethylpyridine or4-(N,N-dimethylamino)pyridine.

The Michael reaction can in typical embodiments be represented by thefollowing two equations:

In the compounds depicted in these equations moieties both Z², Z³ andand Z³ (in the second equation) are an electron withdrawing group suchas one one of NO₂, CN, C(R⁴⁰)O, COOR⁴⁰, CONR⁴⁰R⁴¹ and SO₂R⁴⁰ wherein R⁴⁰and R⁴¹ are independent from one another one of hydrogen, an aliphaticgroup, an alicyclic group, an aromatic group, an arylaliphatic group andan arylalicyclic group, comprising 0 to about 3 heteroatomsindependently selected from the group consisting of N, O, S, Se and Si.R³⁸ and R³⁹ are independently from one another hydrogen, fluorine or oneof an aliphatic, an alicyclic, an aromatic, an arylaliphatic, or anarylalicyclic group that includes 0 to about 3 heteroatoms independentlyselected from the group consisting of N, O, S, Se and Si. R³⁷ is afurther electron withdrawing group as exemplified above or it ishydrogen or flourine or one of an aliphatic group, an alicyclic group,an aromatic group, an arylaliphatic group and an arylalicyclic group,comprising 0 to about 3 heteroatoms independently selected from thegroup consisting of N, O, S, Se and Si. Accordingly, the Michael donorin the Michael addition is for instance in some embodiments a carbonylgroup such as an aldehyde, a ketone or carboxyl group. The Michaelacceptor in the Michael addition is in some embodiments a nitro group, acarbonyl group, a carboxyl group or a sulphonyl group. An example ofvinyl sulphones as the Michael acceptor is depicted in FIG. 13D. In theconjugate addition of isovaleraldehyde to1,1-bis(phenylsulfonyl)ethylene, the desired product could be obtainedin 89% yield and 79% ee without optimization (FIG. 13D). In contrastthereto, proline gave low yield and low ee for this reaction.

It is noted that where both Z² and Z³ are the cyano group poor yieldswith products in undeterminable amounts have been found. The respectivereaction conditions may need to be further analysed. It may neverthelessbe advisable to carry out the Michael reaction depicted in the secondequation with the proviso that not both Z² and Z³ are CN.

Without the intend of being bound by theory it is speculated that uponaddition of a base such as 4-(N,N-dimethylamino)pyridine (DMAP), anacid-base interaction between the carboxylic acid and the amino groupsshould lead to the formation of an ammonium salt, which renders the baseas the stereocontrolling module.

The Michael reaction may for example be carried out in a protic dipolarsolvent, for instance an alcoholic solvent such as ethanol, propanol,isopropanol, butanol, methanol, tert-butanol, isobutanol, tert-amylalcohol, cyclohexanol or phenol. In particular where a basic cocatalystis used, the reaction may also be carried out in an aqueous solvent. TheMichael reaction may also be carried out in an aprotic dipolar solventsuch as tetrahydrofuran, dioxane, pyridine, dimethylformamide oracetonitrile (see above for more examples).

Enantiomers have identical physical and chemical properties except forthe rotation of the plane of polarized light and a potential differentreaction rate with other chiral compounds. The product of an asymmetricMichael reaction may however have more than one stereogenic center (seee.g. FIG. 8), In such a compound each center generally has a pair ofenantiomers (unless a meso form exists) and the obtained product hasdiastereomers. Diastereomers may be defined as stereoisomers that arenot enantiomers. Diastereomers do not merely differ in structure purelyin the left and right handedness of their orientations and accordinglydo not share identical properties. They have different, althoughsimilar, melting points, boiling points, solubilities, reactivity, andall other physical, chemical, and spectral properties. Relative to themain chain of a respective molecule that has diastereomers twonon-hydrogen substituents at two stereoigenic centers may be on the sameside of the plane defined by the main chain. This isomer can be called“syn”. The other isomer, having two non-hydrogen substituents onopposite sides of the plane defined by the main chain, can be called“anti”. This nomenclature is frequently used herein to addressdiastereomers.

The invention is further illustrated by the following exemplaryembodiments and non limiting Examples.

Exemplary Embodiments of the Invention

FIG. 1 structurally compares two compounds of the invention to somenatural products with hexahydropyrrolo[2,3-b]indole skeleton. Thehexahydropyrrolo[2,3-b]indole appears to be a key structural componentof many indole alkaloids exhibiting a diverse range of biologicalactivities (Taniguchi, M, & Hino, T, Tetrahedron (1981) 37, 1487; Bourneet al., 1991, supra; Crich & Banerjee, 2007, supra). This tricylic rigidring system has a stable bowl-shaped conformation.

FIG. 2 depicts a method of preparing a compound of Formula VII, startingfrom a commercially available Nα-protected L-tryptophan compound (cf.also below). A related method, starting from comparable or the sameL-tryptophan compound, results in the formation a compound of FormulaVIA, as shown in FIG. 3.

Based on the tricyclic rigid scaffold of hexahydropyrrolo[2,3-b]indoleskeleton and promising generality, a series of a new class of chiralligands of general Formula (VII) was designed as illustraetd in FIG. 7.This diversified ligand scaffold offers remarkably high tunability inboth steric and electronic properties by judicious selection of thesubstituted R group at the amine N atom and R¹ and R² groups at thetertiary alcohol. Furthermore, two more stereogenic centers wereincorporated as structural analogues in addition to the prolinefeatures, opening up new perspectives in ligands design.

The chiral ligands of Formula (VII) can be used for asymmetriccatalysis, as illustrated in the asymmetric reduction of ketones in FIG.5. FIG. 11 and FIG. 12 depict examples of applications in this regard.An initial study was conducted using chiral ligand 7a with B(OMe)₃ togenerate a borane complex in situ for the asymmetric reduction of2-acetonaphthone at room temperature. Unfortunately, the desired productwas obtained in only 37% e.e. Direct reflux with borane resulted inhigher enantioselectivity (89% e.e.). Screening the differentsubstituting groups showed ethyl carbamate protected ligand 7a to be aparticularly suitable ligand for this reaction. Under the optimizedreaction conditions, ligand 7a was applied to the asymmetric boranereduction of a variety of aromatic ketones (FIG. 11).

As summarized in FIG. 11, high yields and enantioselectivities areobtained for prochiral ketones containing electron-withdrawing orelectron-donating groups. Especially noteworthy is that(R)-3,5-Bistrifluoromethyl phenyl ethanol (BTMP), which is aninteresting chiral building block for a number of pharmaceuticallyinteresting targets such as an NK-1 receptor antagonist (Naud, F, etal., Org. Process Res. Dev. (2007) 11, 519-523; Pollard, D., et al.,Tetrahedron: Asymmetry (2006) 17, 554-559), can be obtained in 99% yieldand 93% e.e. (FIG. 11, entry 10). For aliphatic ketone, moderateenantioselectivity was obtained (FIG. 11, entry 12). Notably, chiralligand 7a can be recovered with 90% yield and reused for 3 times withoutloss of activity and enantioselectivity for the asymmetric reduction of2-acetonaphthone (see in Specific Examples below). For the examplesdepicted in FIG. 11 reactions were performed with 0.5 mmol ketone, 0.6mmol borane and 10% ligand in 2 mL THF at reflux temperature. ^(a)Isolated yield by column chromatography. ^(b) ee determined by HPLCanalysis using Daicel Chiralcel AS-H column. For the examples depictedin FIG. 12 reactions were performed with 0.5 mmol acetonaphthone 0.6mmol borane, 10% ligand in 2 mL of solvent at reflux temperature. ^(a)Isolated yield by column chromatography. ^(b) ee determined by HPLCanalysis using a Daicel Chiralcel AS-H column. ^(c) Catalyst prepared by0.1 eq ligand with 0.12 eq B(OMe)₃ at RT and reduction at RT. ^(d)Catalyst prepared by 0.1 eq ligand with 0.12 eq B(OMe)₃ at refluxcondition and reduction at refulx condition ^(e) Ligand was was recycledonce. ^(f) Ligand was recycled twice ^(g) Ligand was recycled thirdtime.

FIG. 8 illustrates the use of compounds of Formula VIA in asymmetricMichael reactions. On a general basis a Michael reaction is anucleophilic addition to a vinylog carbon-carbon double bond, typicallya 1,4-addition. The reaction can serve in inter alia forming a cycliccompound or extending an aliphatic chain by several carbon atoms in onestep. Accordingly, such a reaction is a suitable model to illustrate thechiral capabilites of a compound. The reaction may for example becarried out by adding a carbonyl compound to an α,β-unsaturated nitrocompound (FIG. 8A), by adding a carbonyl compound to an α,β-unsaturatedcarbonyl compound (FIG. 8B), by adding a nitro compound to anα,β-unsaturaetd nitro compound (FIG. 8C), or by adding a carbonylcompound to an α,β-unsaturaetd sulfonyl compound (FIG. 8D).

Accordingly, in FIG. 8A, FIG. 8B, FIG. 8C and FIG. 8D R²⁰, R²³, R²⁷ andR²⁸ may independently from each other be hydrogen, —OR²⁶, —SiR²⁶, —SR²⁶,—SeR²⁶, an aliphatic group, an alicyclic group, an aromatic group, anarylaliphatic group or an arylalicyclic group. R²¹, R²², R²⁴, R²⁵, R⁴²and R⁴³ may independently from each other be hydrogen, —COOR²⁶, —COSR²⁶,—COSeR²⁶, —CONR²⁶R³⁴, —CN, —COX, —OR²⁶, —SO₂R²⁶ —SiR²⁶, —SR²⁶, —SeR²⁶,an aliphatic group, an alicyclic group, an aromatic group, anarylaliphatic group or an arylalicyclic group. X is halogen. R²⁶ and R³⁴are independent from one another one of hydrogen, an aliphatic group, analicyclic group, an aromatic group, an arylaliphatic group or anarylalicyclic group. R²² in FIG. 8E has the same meaning as above.

FIG. 10A compares the ¹H-NMR spectra of pure DMAP (top panel), theisolated compound of Formula VIA (lower panel), and a mixture of bothcompounds (center panel). Note the significant changes in chemicalshift: protonation of DMAP causes signals to be moved to lower field,whereas signals of the catalyst are moved to higher field, whichindicate the salt formation. As can be taken from FIG. 10B and FIG. 10Cthe catalyst is stable in water over extended periods of time.

FIG. 13 and FIG. 14 illustrate the catalytic asymmetric Michael additionof propanal to nitroalkenes. With chiral catalyst (10) in hand, theinventors proceeded to investigate itsapplication for asymmetriccatalysis. To demonstrate the efficiency of (10), the enantioselectiveMichael addition of aldehydes (for recent reviews see (a) Moss& S, &Alexakis, A, Chem. Commun. (2007) 3123. (b) Vicario, J L, et al.,Synthesis (2007) 2065. (c) Tsogoeva, S B, Eur. J. Org. Chem. (2007)1701. For some representatives, see: (e) Mase, N, et al., J. Am. Chem.Soc. (20069 128, 4966. (f) Hayashi, Y, et al., Angew. Chem. Mt. Ed.(2005) 44, 4212. (g) Wang, W, et al., Angew. Chem. Mt. Ed. (2005) 44,1369. (h) Palomo, C E, et al., Angew. Chem. Int. Ed. (2006) 45, 5984.(i) Palomo, C, et al., Angew. Chem. Int. Ed. (2006) 45, 5984) tonitroalkenes was selected as the testing ground since nitroalkanes areversatile synthetic intermediates.

The desired product could be obtained in 86% yield and 96% e.e. in thepresence of 10 mol % catalyst (10) using 2 equiv propanal at roomtemperature in MeOH (entry 1 of FIG. 13). In contrast, catalysts 11, 12and 13 gave much less desirable results in MeOH (FIG. 13, entries 2-4).Without being bound by theory, these results demonstrate that it isproline's skeleton and not the hydrogen bonding interaction whichaccount for its failure in this reaction. It was further shown that whena base such as DMAP is added, an acid-base interaction between thecarboxylic acid and the amine groups leads to an ammonium salt whichrenders the base as the stereocontrolling module, hence alleviating theneed for tedious chemical structural modification. This is inline withthe concept of the self-assembly of organocatalysts proposed recently[Clarke, M L, & Fuentes, J A, Angew. Chem. Int. Ed. (2007) 46, 930;Mandal T, & Zhao, C G, Angew. Chem. Int. Ed. (2008) 47, 7714-7717;Schmuck, C, & Wienand, W, J. Am. Chem. Soc. (2003) 125, 452; Gac, S L,et al., Tetrahedron (2007) 63, 10721]. More than 99% e.e. was achievedwhen DMAP was added and the catalyst loading could be decreased to aslow as 2 mol % (entries 4 & 5 of FIG. 13). ¹H NMR revealed that the saltwas formed rapidly and quantitatively with significant chemical shift ofall the protons (see FIG. 10). Both (10) and (10)/DMAP are soluble inwater and are stable as shown by 1H NMR. More importantly, the (10)/DMAPcatalyst could also catalyze the reaction in water (entry 7 of FIG. 13).Very low yield was obtained when using brine as solvent (entry 8 of FIG.13). However, no reaction was observed using either (11)/DMAP, (12)/DMAPor (13)/DMAP, or (10) itself in pure water (entries 9-12 of FIG. 13).Next, various substrates were examined and the reaction exhibited broadapplicability with respect to both the Michael acceptor and the donor.Theadducts were obtained in almost optically pure form (99% ee) and withgood syn diastereoselectivity. The stereochemistry was confirmed byX-ray crystal structure of one of the products (see below and FIG. 16).Both aromatic and aliphatic aldehyes, aryl- and alkyl-substitutednitroalkenes gave the desired products in good yields and excellentenantioselectivities (entries 1-11 of FIG. 14). For more bulkyisobutyraldehyde, which was found to be a poor nucleophile in only 68%ee using 20 mol % diarylprolinol ether catalyst [Hayashi, Y, et al.,Angew. Chem. Int. Ed. (2005) 44, 4212], were obtained with 92-95% eewith various nitrostyrenes with the respective exemplary catalyst(entries 12-14 of FIG. 14). In view of the high efficiency and highcatalytic activity shown both in organic solvents and water with lowcatalyst loading, the catalyst (10)/DMAP can be seen as an “artificialenzyme”. Most of the earlier reports for such a reaction were carriedout at 0° C. or even lower temperature with 10 equiv aldehydes. Usingcatalyst (10), only 2 equiv of aldehydes was employed and excellent eecould be obtained at room temperature.

To probe the mechanism of this reaction, different possible conformersof the enamine intermediate were subjected to DFT calculation todetermine the lowest energy conformation (see the Examples below fordetails). As expected, the ethyl carbamate group control the geometry ofthe enamine to adopt the syn enamine conformation (FIG. 2). From thisconformer, it can be seen that at the Si face of the enamine, there areseveral highly electronegative atoms such as O and N whichcould functionas hydrogen bond acceptors. Therefore when the enamine is immersed intoprotic solvents such as methanol and water, the Si face is expected todevelop strong hydrogen-bond networks which eventually block the attackof nitrostyrene from this side (Wang, J, et al., Chem. Eur. J. (2006)12, 4321; Chen, X-H, et al., Chem. Eur. J. (2007) 13, 689). On thisbasis, nitrostyrene will attack the enamine from the less hindered Reface via transition state (XXXA), where a water molecule is probablyinvolved by forming hydrogen bonds with the CO₂H group and NO₂ whichwill lead to the desired (S, R) product (FIG. 9A) (Seebach, D, &Golinski, J, Helv. Chim. Acta (1981) 64, 1413; Seebach, D, et al., Helv.Chim. Acta (1985) 68, 162). The activation energy of transition state(XXXA) is 64.61 kJ/mol lower than that of transition state (XXXB)without the water molecule as hydrogen-bond bridge. The whole system isstabilized by hydrogen bonds. The transition state (XXXC), which isconsistent with Seebach's model, is also calculated and the energy of(XXXC) is 7.91 kJ/mol higher than that of the transition state (XXXA)(see the Examples below). This proposal is supported by the followingexperimental results: (1) methyl ester derivative 6a (cf. FIG. 4A) orthe phenyl ester derivative could not catalyze the reaction with orwithout acid additive in MeOH or H₂O, which indicate the possibleactivation of nitrostyrene by the carboxylic acid (cf. the scheme ofFIG. 13B):

(2) the reaction was much slower in aprotic solvent such as DMSO and DMFwhich implies that H₂O may be involved in the reaction throughhydrogen-bonding interaction. Although the role of DMAP is not clear atthis moment, the DMAP salt was found to improve the solubility of thecatalyst and could also function as phase transfer catalyst when thereaction was carried out in water. Without being bound by theory, thisstructurally rigid tricyclic skeleton provides a well-organizedenvironment for asymmetric induction as well as a hydrophobic pocket toenable this reaction to proceed smoothly in water. As for catalysts 11,12 and 13 (cf. FIG. 13A), they could not satisfy the above criteria.

EXAMPLES General Methods

Experiments involving moisture and/or air sensitive components wereperformed in oven-dried glassware under a positive pressure of nitrogenusing freshly distilled solvents. Commercial grade solvents and reagentswere used without further purification with the following exceptions:Dichloromethane was distilled from calcium hydride. THF was distilledfrom sodium and benzophenone. Hexane, ethyl acetate were fractionallydistilled.

Borane-methyl sulfide complex was purchased from Aldrich. Aromaticketone were purchased from Aldrich or prepared from Grignard reagentsaddition to corresponding aromatic aldehyde, then followed by standardIBX oxidation reaction. All the ketone and ligands were dried two timeswith anhydrous THF prior to use.

Analytical thin layer chromatography (TLC) was performed using Merck 60F254 precoated silica gel plate (0.2 mm thickness). Subsequent toelution, plates were visualized using UV radiation (254 nm) onSpectroline Model ENF-24061/F 254 nm. Further visualization was possibleby staining with basic solution of potassium permanganate or acidicsolution of ceric molybdate.

Flash chromatography was performed using Merck silica gel 60 withfreshly distilled solvents. Columns were typically packed as slurry andequilibrated with the appropriate solvent system prior to use.

Infrared spectra were recorded on a Bio-Rad FTS 165 FTIR spectrometer.The oil samples were examined under neat conditons.

High Resolution Mass (HRMS) spectra were obtained using Finnigan MAT95XPGC/HRMS (Thermo Electron Corporation).

Proton nuclear magnetic resonance spectra (¹H NMR) were recorded on aBruker Avance DPX 300 and Bruker AMX 400 spectrophotometer (CDCl₃ assolvent). Chemical shifts for ¹H NMR spectra are reported as S in unitsof parts per million (ppm) downfield from SiMe₄ (δ 0.0) and relative tothe signal of chloroform-d (δ 7.2600, singlet). Multiplicities weregiven as: s (singlet); d (doublet); t (triplet); q (quartet); dd(doublets of doublet); ddd (doublets of doublets of doublet); dddd(doublets of doublets of doublets of doublet); dt (doublets of triplet);or m (multiplets). The number of protons (n) for a given resonance isindicated by nH. Coupling constants are reported as a J value in Hz.Carbon nuclear magnetic resonance spectra (¹³C NMR) are reported as S inunits of parts per million (ppm) downfield from SiMe₄ (δ 0.0) andrelative to the signal of chloroform-d (δ 77.0, triplet). The proportionof diastereomers and geometric isomers was determined from theintegration of ¹H NMR and ¹³C NMR spectra.

Enantioselectivities were determined HPLC analysis employing a DaicelChiracel column at 25° C. Optical rotation was measured using a JASCOP-1030 Polarimeter equipped with a sodium vapor lamp at 589 nm.Concentration is denoted as c and was calculated as grams per deciliters(g/100 mL) whereas the solvent. Absolute configuration of the productswas determined by comparison with known compounds. X-ray crystallogphyanalysis was performed on Bruker X8 APEX X-Ray diffractometer.

General Procedure for the Catalytic Asymmetric Michael Addition ofAldeydes to Nitrostyrene

To a 4 mL sample vial equipped with a magnetic stirring bar, the mixtureof catalyst (2.7 mg, 0.01 mmol), DMAP (1.2 mg, 0.01 mmol), nitroalkene(0.2 mmol) aldehyde (0.4 mmol) were added followed by MeOH or water (0.5mL) at room temperature. The reaction mixture was stirred for the timeindicated in FIG. 14, and then it was directly purified by preparativeTLC (Hexane/EA, 4/1) to afford the product as inseparable isomers. Bothenantiomeric excess and diastereomeric ratio (syn/anti) were determinedby HPLC using chiral AS-H, AD-H or OD-H columns unless otherwise statedin comparison with the literature reported values.

General Procedure for the Enantioselective Ketone Reduction

To an oven-dried 10 mL round-bottom flask equipped with a magneticstirring bar was added new chiral ligand 7a (0.07 mmol, 0.10 equiv). Theligand was azeotropically dried with anhydrous THF twice (2 mL×2) priorto the addition of 1.5 mL of THF. Then BH₃□Me₂S (0.087 mmol, 10 mol/L)was added under nitrogen at room temperature and the mixture was stirredat 80° C. for 3 h. A solution of ketone (0.7 mmol) in dry THF (0.5 mL)was added dropwise by syringe pump over a period of 1 h at refluxtemperature. Then the reaction mixture was cooled and quenched bydropwise addition of methanol (5 mL). After concentration by rotatoryevaporation, the product was purified by column chromatography on silicagel (hexane-ethyl acetate 5:1) to afford the corresponding secondaryalcohol. The enantiomeric excess was determined by chiral HPLC analysisemploying a Daicel Chiracel column.

A general scheme of the preparation and characterization of a tryptophanderivative is shown in FIG. 2. FIG. 15 depicts further examples, showingthe synthesis of chiral ligands 7a-h.

Synthesis of (S)-N-benzyloxycarbonyl-L-tryptophan methyl ester (2a)

To a stirred suspension of (S)-N-benzyloxycarbonyl-L-tryptophan 1a (2.45g, 7.2 mmol) in 10 ml anhydrous CH₂Cl₂, was added DMAP (0.1 g, 0.82mmol) and methanol (0.28 g, 11.8 mmol). At 0° C., DCC in CH₂Cl₂ solutionwas slowly added to the mixture and then it was allowed to warm to roomtemperature and stirred overnight. After twice filtration andevaporation, the residue was purified by flash column chromatography(n-hexane/EA, 4:1 to 2:1) and afforded the desired product (S)-2a as acolourless oil (2.5 g, 98%).

R_(f)=0.19 (EA:Hexane=1:2)

¹H NMR (300 MHz, CDCl₃): δ 8.94 (br, 1H), 7.49 (d, J=7.7 Hz, 1H),7.25-6.98 (m, 9H), 6.81 (s, 1H), 5.84 (d, J=8.7 Hz, 1H), 4.98 (d, J=3.2Hz, 2H), 4.68 (q, J=7.3 Hz, 1H), 3.25 (s, 3H), 3.21 (m, 2H);

¹³C NMR (75 MHz, CDCl₃): δ 172.2, 155.9, 141.8, 136.8, 134.9, 128.6,127.8, 126.9, 123.4, 122.3, 120.0, 118.4, 112.1, 109.4, 67.0, 65.1,55.1;

FTIR (KBr, neat): v 1707, 1508, 1456, 1436, 1215, 742 □cm⁻¹;

HRMS (El) calcd. for C₂₀H₂₀O₄N₂ 352.1418, found [M]⁺ 352.1425;

(2S)-1-benzyl-2-methyl-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1,2(2H)-dicarboxylate(3a)

N-benzyloxycarbonyl-L-tryptophan methyl ester (S)-2 (1.34 g, 3.8 mmol)was dissolved in 5 ml TFA and stirred for two days, then the solutionwas added dropwise to a vigorously stirred two phase system consistingof saturated 100 ml Na₂CO₃ and 100 ml CH₂Cl₂ at 0° C. The two phase wasseparated and the aqueous solution was extracted with CH₂Cl₂ (30 ml×3).The combined organic phases were washed with brine and dried withanhydrous MgSO₄ and purified with flash column chromatography(EA/Hexane, 1:7-1:4) to give the product as colorless oil (0.8 g, 60%)which rapidly darkened on standing in air.

Major isomer:

R_(f)=0.32 (EA:Hexane=1:4);

¹H NMR (400 MHz, CDCl₃): δ 7.42-7.24 (m, 5H), 7.05-6.99 (m, 2H), 6.68(q, J=8.9 Hz, 1H), 6.60 (d, J=7.6 Hz, 1H), 5.59 (t, J=6.6 Hz, 1H),5.30-5.09 (m, 2H), 3.92 (q, J=6.5 Hz, 1H), 3.19 (s, 1H, CH₃), 3.10 (s,2H, CH₃), 2.65-2.54 (m, 2H);

¹³C NMR (100 MHz, CDCl₃): δ 172.0, 154.6, 150.1, 136.2, 129.0, 128.6,128.4, 127.6, 127.5, 127.4, 127.0, 124.0, 118.7, 109.1, 77.4, 67.0,59.1, 51.9, 45.0, 34.0;

FTIR (KBr, neat): v 1732, 1712, 1602 cm⁻¹,

HRMS (EI) calcd. for C₂₀H₂₀O₄N₂ 352.1418, found [M]⁺352.1413;

(2S,3aR,8aS)-1-benzyl-8-ethyl-2-methyl-3,3a-dihydropyrrolo[2,3-b]indole-1,2,8(2H,8aH)-tricarboxylate(4a)

(2S)-1-benzyl-2-methyl-3,3a,8,8a-tetrahydropyrrolo[2,3-b]indole-1,2(2H)-dicarboxylate3a (0.8 g, 2.27 mmol) was dissolved in 5 ml THF, then Na₂CO₃ (0.36 g,3.40 mmol) and 5 ml H₂O was added. At 0° C., ethyl chloroformate (0.22ml, 2.26 mmol) was slowly added to the solution and stirred overnight.10 ml water was added and the aqueous solution was extracted with EA (5ml×3). The combined organic phases were washed with brine and dried withanhydrous MgSO₄ and purified with flash column chromatography(EA/Hexane,1:4-1:2) to afford the desired product as colorless oil (0.77g, 80%).

R_(f)=0.43 (EA:Hexane=1:2);

¹H NMR (300 MHz, CDCl₃): δ 7.66 (d, J=7.5 Hz, 1H), 7.38-7.10 (m, 7H),6.99 (t, J=7.4 Hz, 1H), 6.49 (d, J=6.5 Hz, 1H), 5.19 (s, 2H), 4.67 (d,J=8.5 Hz, 1H), 4.33-4.17 (br, 1H), 4.00 (t, J=7.1 Hz,1H), 3.13 (s, 3H),2.65-2.43 (m, 2H),1.35-1.23 (br, 3H);

¹³C NMR (75 MHz, CDCl₃): δ 171.1, 153.6, 152.9, 142.2, 135.9, 130.8,128.2, 128.0, 127.9, 127.7, 127.5, 127.5, 123.5, 122.9, 116.2, 77.1,66.7, 61.3, 58.9, 51.4, 44.5, 33.2, 13.9;

FTIR (KBr, neat): v 1728, 1712, 1697, 1604, 1483 cm⁻¹;

HRMS (El) calcd. for C₂₃H₂₄O₆N₂ 424.1629, found [M]⁺ 424.1619;

(2S,3aR,8aS)-8-ethyl-2-methyl-1,2,3,3a-tetrahydropyrrolo[2,3-b]indole-2,8(8aH)-dicarboxylate(6a)

(2S,3aR,8aS)-1-benzyl-8-ethyl-2-methyl-3,3a-dihydropyrrolo[2,3-b]indole-1,2,8(2H,8aH)-tricarboxylate4a (0.77 g, 1.82 mmol) was dissolved in 5 ml CH₃OH and 10%

Pd/C (0.19 g, 0.18 mmol) was added to the solution and stirred overnightunder H₂ balloon at RT. When TLC showed the full depletion of thestarting material, the suspension was filtered on celite and the solventwas evaporated, the residue was purified with flash columnchromatography (EA/hexane, 1:4-1:2) to give the product as colorless oil(0.48 g, 90%)

Major isomer:

R_(f)=0.62 (EA:Hexane=1:2);

¹H NMR (300 MHz, CDCl₃): δ 7.86 (d, J=7.5 Hz, 0.5H), 7.47-7.27 (m,0.5H), 7.24 (d, J=7.4 Hz, 2H), 7.05 (t, J=7.5 Hz, 1H), 5.80 (d, J=6.8Hz, 1H), 4.45 (q, J=6.6 Hz, 2H), 3.99 (d, J=7.6 Hz, 2H), 3.41 (s, 3H),2.73-2.64 (m, 1H), 2.49 (d, J=11.2 Hz, 1H), 1.50 (t, J=6.0 Hz, 3H);

¹³C NMR (75 MHz, CDCl₃): δ 174.1, 152.5, 128.7, 127.8, 126.1, 124.5,122.8, 114.3, 78.4, 60.9, 57.8, 50.7, 43.7, 34.8, 15.1;

FTIR (KBr, neat): v 1732, 1712, 1602, 1487 cm⁻¹,

HRMS (EI) calcd. for C₁₅H₁₈O₄N₂ 290.1261, found [M]⁺ 290.1249;

(2S,3aR,8aS)-ethyl2-(hydroxydiphenylmethyl)-1,2,3,3a-tetrahydropyrrolo[2,3-b]-indole-8(8aH)-carboxylate(7a)

At 0° C., to a solution of(2S,3aR,8aS)-8-ethyl-2-methyl-1,2,3,3a-tetrahydro-pyrrolo[2,3-b]indole-2,8(8aH)-dicarboxylate6 (0.48 g, 1.65 mmol) in 5 ml THF was added dropwise 2M phenyl magnesiumchloride (2.1 ml, 4.2 mmol) in THF solution and stirred for half anhour, then quenched by 5 ml water. The two phase was separated and theaqueous solution was extracted with EA (5 ml×3). The combined organicphases were washed with brine and dried with anhydrous MgSO₄ andpurified with flash column chromatography (EA/hexane, 1:10) to give theproduct as colorless solid (205 mg, 30%).

R_(f)=0.85 (EA:Hexane=1:6);

¹H-NMR (400 MHz, CDCl₃): δ 7.56 (d, J=7.6 Hz, 2H), 7.44 (d, J=7.4 Hz,2H), 7.32-7.14 (m, 7H), 7.03 (d, J=7.2 Hz, 1H), 6.94 (t, J=9.3 Hz, 1H),5.65 (br, 1H), 4.47 (t, J=6.6 Hz, 1H), 4.26 (br, 2H), 4.04 (br, 1H),3.74 (q, J=7.2 Hz, 1H), 2.04 (br, 1H), 1.84-1.76 (m, 1H), 1.43-1.32 (m,1H), 1.27-1.11 (m, 3H);

¹³C-NMR (100 MHz, CDCl₃): δ 154.0, 147.2, 144.6, 128.4, 128.0, 127.9,126.9, 126.6, 125.7, 125.3, 124.6, 124.2, 122.9, 114.9, 75.7, 63.8,44.1, 32.8, 22.7, 14.1;

FTIR (KBr, neat): v 1699, 1487, 1381, 1307 cm⁻¹,

HRMS (EI) calcd. for C₂₆H₂₆O₃N₂ 414.1938, found [M]⁺ 414.1915;

Synthesis of (S)-benzyl2-(benzyloxycarbonylamino)-3-(1H-indol-3-yl)propanoate (2)

To a stirred suspension of (S)-(1) (2.45 g, 7.2 mmol) in 10 ml anhydrousCH₂Cl₂, was added DMAP (88 mg, 0.72 mmol) and benzyl alcohol (1.28 g,11.8 mmol). DCC (1.48 g, 7.2 mmol) in 5 mL CH₂Cl₂ was slowly added tothe mixture at 0° C. and the mixture was stirred overnight with slowwarm to RT. The white precipitate was filtered, then remove the solventto afford the product as colourless oil (3 g, 98%). [α]_(D) ²⁰=50(c=1.0, CHCl₃, 365 nm).

R_(f)=0.29 (EA:Hexane=1:2);

¹H NMR (400 MHz, CDCl₃): δ 8.26 (br, 1H), 7.56 (d, J=8.0 Hz, 1H),7.41-7.33 (m, 9H), 7.26-7.20 (m, 3H), 7.12 (t, J=8.0 Hz, 1H), 6.76 (d,J=2.0 Hz,1H), 5.47 (d, J=8.0 Hz, 1H), 5.18-5.10 (m, 4H), 4.82 (q, J=8.0Hz, 1H), 3.34 (d, J=5.1 Hz, 2H);

¹³C NMR (100 MHz, CDCl₃): δ 171.8, 155.8, 136.1, 136.0, 135.1, 128.5,128.4, 128.3, 128.0, 127.5, 127.4, 126.9, 122.9, 122.0, 119.5, 118.5,111.2, 109.4, 67.1, 66.8, 54.6, 27.8;

FTIR (neat): v 3395, 3343, 1742, 1458, 1377, 721 □cm⁻¹;

HRMS (ESI) calcd. for C₂₀H₂₀O₄N₂ 429.1814 [M+H]⁺, found 429.1821 [M+H]⁺.

Synthesis of (2S,3aR,8aR)-dibenzyl3,3a,8,8a-tetrahydropyrrolo[2,3-b]indol-1,2 (2H)-dicarboxylate (3)

N-benzyloxycarbonyl-L-trptophan benzyl ester (2) (1.18 g, 2.75 mmol) wasdissolved in 5 ml TFA and stirred for two days, then the solution wasadded dropwise to a vigorously stirred two-phase system consisting of100 mL saturated Na₂CO₃ and 100 mL CH₂Cl₂, The two phase was separatedand the aqueous solution was extracted with CH₂Cl₂ (30 mL×3). Thecombined organic phases were washed with brine and dried with anhydrousMgSO₄ and purified with column chromatography (ethylacetate/hexane=1:7-1:4) to give the poduct as colorless oil (1.04 g,88%) which rapidly darkened on standing in air.

Major isomer:

R_(f)=0.34 (EA:Hexane=1:2);

¹H NMR (400 MHz, CDCl₃): δ 7.40-7.19 (m, 8H), 7.13-1.12 (m, 1H),7.07-7.04 (m, 1H), 7.02-6.97 (m, 2H),6.67 (t, J=8.0 Hz, 1H), 6.49 (d,J=8.0 Hz, 1H), 5.60 (d, J=8.0 Hz, 1H), 5.24 (s, 1H), 5.04 (d, J=43,12Hz, 1H), 4.73 (d, J=12 Hz, 1H), 4.56 (dd, J=7.6, 2.3 Hz, 1H), 4.32 (d,J=12.3 Hz, 1H), 3.90 (q, J=6.5 Hz, 1H), 2.66-2.53 (m, 2H);

¹³C NMR (100 MHz, CDCl₃): δ 171.3, 154.7, 149.9, 135.5, 128.6, 128.4,128.3, 128.0,128.0, 128.0, 127.9, 127.9, 127.8, 124.0, 118.7, 109.1,77.4, 67.1, 66.7, 59.1, 45.0, 34.4;

[α]_(D) ²⁰=52.9 (c=1.8, CHCl₃, 365 nm);

FTIR (neat): v 3032, 2953, 1751, 1701, 1610, 1416, 731 □cm⁻¹,

HRMS (ESI) calcd. for C₂₀H₂₀O₄N₂ 429.1814 [M+H]⁺, found 429.1818 [M+H]⁺.

Synthesis of (2S,3aR,8aS)-1,2-dibenzyl 8-ethyl3,3a-dihydropyrrolo[2,3-b]indole-1,2,8(2H,8aH)-tricarboxylate (4)

(S)-(3) (0.11 g, 0.26 mmol) was dissolved in 6 mL THF, then Na₂CO₃(1.06g, 10 mmol) in 6 ml H₂O was added. Ethyl chloroformate (0.25 mL, 2.6mmol) was slowly added to the solution at 0° C. After stirringovernight, 10 ml water was added and the obtained two phases wereseparated. The aqueous solution was extracted with EA (5 mL×3). Thecombined organic phases were washed with brine and dried with anhydrousMgSO₄ and purified with column chromatography (ethylacetate/hexane=1;5-1:2) to give the product as colorless oil (0.11 g,86%).

R_(f)=0.24 (EA:Hexane=1:2);

¹H NMR (300 MHz, CDCl₃): δ 7.53 (br, 1H), 7.27-7.23 (m, 8H), 7.14 (t,J=8.3 Hz, 1H), 7.09-7.04 (m, 4H), 6.94 (t, J=7.5 Hz, 1H), 6.47 (d, J=6.2Hz, 1H), 5.14 (q, J=15 Hz, 2H), 4.72-4.68 (m, 2H), 4.36 (d, J=12.6 Hz,1H),3.96 (t, J=6.8 Hz, 1H), 2.64-2.49 (m, 2H), 1.26-1.20 (m, 3H);

¹³C NMR (75 MHz, CDCl₃): δ 170.9, 154.1, 153.5, 142.7, 136.4, 135.3,131.2, 128.8, 128.6, 128.5, 128.4, 128.1, 127.9, 127.6, 124.0, 123.5,116.9, 67.4, 66.8, 61.9, 59.6, 45.0, 33.9, 14.5;

[α]_(D) ²⁰=−10.8 (c=1.04, CHCl₃, 365 nm);

FTIR (neat): v 3018, 2957, 1717, 1605, 1483, 748 □cm⁻¹,

HRMS (ESI) calcd. for C₂₉H₂₉O₆N₂ 501.2026 [M+H]⁺, found 501.2018 [M+H]⁺.

Synthesis of (2S,3aR,8aS-dibenzyl 8-ethoxycarbonyl1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylic acid (10)

4 (5 g, 10 mmol) was dissolved in 20 mL methanol, and Pd/C (106 mg, 1mmol) was added to the solution. After stirring overnight with the H₂balloon, the obtained mixture was filtered with celite and the solventevaporated to give the product as colorless oil. Then CH₂Cl₂ was added,the white solid precipitated and a further filtration gave the productas white solid (2.76 g, 100%).

R_(f)=0.59 (CH₂Cl₂:CH₃OH=1:4);

¹H NMR (400 MHz, CD₃OD): δ 7.77, 7.52 (br, 1H), 7.26-7.20 (m, 2H), 7.04(t, J=7.6 Hz), 5.86 (d, J=8.6 Hz, 1H), 4.38 (br, 2H), 4.14-4.09 (m, 1H),4.02 (t, J=7.6 Hz, 1H), 2.88-2.80 (m, 1H), 2.31-2.27 (m, 1H), 1.41 (t,J=6.7 Hz, 3H);

¹³C NMR (100 MHz, CD₃OD): δ 172.5, 152.1, 140.9, 131.5, 128.1, 124.2,123.0, 113.6, 77.9, 62.0, 60.0, 44.0, 35.1, 13.4;

[α]_(D) ²⁰=−15.9 (c=0.4, CH₃OH, 365 nm);

FTIR (neat): v 3177, 2725, 1721, 1629, 1570, 1462, 1377, 760, 721 □cm⁻¹,

HRMS (ESI) calcd. for C₁₄H₁₇O₄N₂ 277.1188 [M+H]⁺, found [M]⁺ 277.1188[M+H]⁺.

(2S,3R)-2-Methyl-4-nitro-3-phenylbutanal

The title compound was prepared from propionaldehyde and(E)-(2-nitrovinyl)benzene according to the general procedure. Bothenantiomeric excess and diastereomeric ratio were determined by HPLCwith an OD-H column at 210 nm (2-propanol:hexane=10:90), 1.0 mL/min;major enantiomer t_(major)=22.06 min, minor enantiomer t_(minor)=30.05min. [α]_(D) ²⁰=−28.8 (c=2.2, CHCl₃).

R_(f)=0.18 (EA:Hexane=1:4);

¹H NMR (300 MHz, CDCl₃): δ 9.72 (d, J=1.5 Hz, 0.85H) (syn isomer), 9.72(d, J=1.5 Hz, 0.15H) (anti isomer), 7.37-7.29 (m, 3H), 7.22-7.16 (m,2H), 4.83-4.65 (m, 2H), 3.87-3.77 (m, 1H), 2.87-2.72 (m, 1H), 1.21 (d,J=7.3 Hz, 0.5H) (anti isomer), 1.01 (d, J=7.3 Hz, 2.5H) (syn isomer);

¹³C NMR (75 MHz, CDCl₃): δ 202.3, 136.6, 129.1, 128.1, 78.1, 48.4, 44.0,12.1;

IR (thin film) v/cm⁻¹: 3030, 2970, 2931, 1724, 1603, 1552, 1454, 1379,758, 702;

HRMS (ESI-TOF): Calcd. for C₁₁H₁₄NO₃: 208.0974 [M+H]⁺, Found: 208.0971[M+H]⁺.

(2S,3R)-3-(4-Bromophenyl)-2-methyl-4-nitrobutanal

The title compound was prepared from propionaldehyde and(E)-1-bromo-4-(2-nitrovinyl)benzene according to the general procedure.Both enantiomeric excess and diastereomeric ratio were determined byHPLC with an AD-H column at 230 nm (2-propanol:hexane=5:95), 1.0 mL/min;major enantiomer t_(major)=18.59 min, t_(minor)=13.77 min. [α]_(D)²⁰=−24.6 (c=2.1, CHCl₃).

R_(f)=0.18 (EA:Hexane=1:4);

¹H NMR (300 MHz, CDCl₃) δ 9.69 (d, J=1.5 Hz, 0.8H) (syn isomer), 9.52(d, J=1.5 Hz, 0.2H) (anti isomer), 7.50-7.46 (m, 2H), 7.12-7.05 (m, 2H),4.82-4.56 (m, 2H), 3.84-3.74 (m, 1H), 2.83-2.70 (m, 1H), 1.21 (d, J=7.3Hz, 0.6H) (anti isomer), 1.00 (d, J=7.3 Hz, 2.4H) (syn isomer);

¹³C NMR (75 MHz, CDCl₃) δ 201.8, 135.7, 132.3, 129.8, 122.1, 77.8, 48.2,43.5, 12.2;

IR (thin film) v/cm⁻¹: 2976, 2935, 2879, 1726, 1553, 1489, 1377, 1010,779, 717;

HRMS (ESI-TOF) Calcd. for C₁₁H₁₃NO₃Br: 286.0079 [M+H]⁺, Found: 286.0081[M+H]⁺.

(2S,3R)-3-(4-Methoxyphenyl)-2-methyl-4-nitrobutanal

The title compound was prepared from propionaldehyde and(E)-1-methoxy-4-(2-nitrovinyl)benzene according to the generalprocedure. Both enantiomeric excess and diastereomeric ratio weredetermined by HPLC with an AS-H column at 230 nm(2-propanol:hexane=5:95), 1.0 mL/min; major enantiomer t_(majo)=42.10min, minor enantiomer t_(minor)=60.77 min. [α]_(D) ²⁰=−4.6 (c=1.3,CHCl₃).

R_(f)=0.13 (EA:Hexane=1:4);

¹H NMR (300 MHz, CDCl₃) δ 9.70 (d, J=1.4 Hz, 0.6H) (syn isomer), 9.53(d, J=1.4 Hz, 0.4H) (anti isomer), (7.27-7.07 (m, 2H), 6.87-6.67 (m,2H), 4.78-4.60 (m, 2H), 3.78 (s, 3H), 3.78-3.73 (m, 1H), 2.81-2.69 (m,1H), 1.21 (d, J=7.2 Hz, 1.11H) (anti isomer), 0.99 (d, J=7.2 Hz, 1.89H)(syn isomer);

¹³C NMR (75 MHz, CDCl₃) δ 202.5, 129.2, 129.1, 128.3, 114.4, 78.3, 55.2,48.6, 43.3, 12.0;

IR (thin film) v/cm⁻¹: 2978, 2937, 2839, 1726, 1612, 1557, 1514, 1379,1253, 1182, 1033, 833, 725;

HRMS (ESI-TOF) Calcd. for C₁₂H₁₆NO₄: 238.1079 [M+H]⁺, Found: 238.1081[M+H]⁺.

(2S,3S)-3-(Furan-2-yl)-2-methyl-4-nitrobutanal

The title compound was prepared from propionaldehyde and(E)-2-(2-nitro-vinyl)furan according to the general procedure. Bothenantiomeric excess and diastereomeric ratio were determined by HPLCwith an AD-H column at 220 nm (2-propanol:hexane=0.8:99.2), 1.0 mL/min;major enantiomer t_(major)=30.44 min, minor enantiomer t_(minor)=26.29min. [α]_(D) ²⁰=−20 (c=2.0, CHCl₃).

R_(f)=0.17 (EA:Hexane=1:4);

¹H NMR (400 MHz, CDCl₃) δ 9.70 (s, 0.87H) (syn isomer), 9.62 (s, 0.13H)(anti isomer), 7.35 (s, 1H), 6.30-6.29 (m, 1H), 6.17 (d, J=3.22 Hz, 1H),4.77-4.67 (m, 2H), 4.13-4.05 (m, 1H), 2.87-2.76 (m, 1H), 1.22 (d, J=7.31Hz, 0.48H) (anti isomer), 1.06 (d, J=7.31 Hz, 2.52H) (syn isomer);

¹³C NMR (100 MHz, CDCl₃) δ 201.6, 149.9, 142.7, 110.4, 108.7, 75.8,47.1, 37.6, 11.0;

IR (thin film) v/cm⁻¹: 3152, 3123, 2974, 2938, 2880, 1724, 1557, 1458,1377, 1150, 1013, 814, 741, 702;

HRMS (ESI-TOF) Calcd. for C₉H₁₂NO₄: 198.0766 [M+H]⁺, Found: 198.0761[M+H]⁺.

(2S,3R)-2-Ethyl-4-nitro-3-phenylbutanal

The title compound was prepared from butyraldehyde and(E)-(2-nitrovinyl)-benzene according to the general procedure. Theenantiomeric ratio was determined by HPLC with an OD-H column at 220 nm(2-propanol:hexane=5:95), 1.0 mL/min; major enantiomer t_(major)=40.61min, minor enantiomer t_(minor)=51.74 min. The diastereomeric excess wasdetermined by ¹H NMR. [α]_(D) ²⁰=−99.5 (c=1.1, CHCl₃).

R_(f)=0.27 (EA:Hexane=1:4);

¹H NMR (300 MHz, CDCl₃) δ 9.71 (d, J=2.5 Hz, 0.91H) (syn isomer), 9.47(d, J=2.5 Hz, 0.09H) (anti isomer), 7.36-7.27 (m, 3H), 7.20-7.17 (m,2H), 4.80-4.59 (m, 2H), 3.84-3.75 (m, 1H), 2.72-2.64 (m, 1H), 1.55-1.43(m, 2H), 1.21 (t, J=7.5 Hz, 0.33H) (syn isomer), 0.82 (t, J=7.5 Hz,2.67H) (anti isomer);

¹³C NMR (75 MHz, CDCl₃) δ 203.2, 136.8, 129.1, 128.0, 78.5, 42.6, 20.3,10.6;

IR (thin film) v/cm⁻¹: 2967, 2936, 2878, 1720, 1553, 1456, 1379, 1244,758, 702;

HRMS (ESI-TOF) Calcd. for C₁₂H₁₆NO₃: 222.1130 [M+H]⁺, Found: 222.1129[M+H]⁺.

(2S,3R)-2-methyl-3-(naphthalen-1-yl)-4-nitrobutanal

The title compound was prepared from butyraldehyde and(E)-1-(2-nitrovinyl)naphthalene according to the general procedure. Bothenantiomeric excess and diastereomeric ratio were determined by HPLCwith an AD-H column at 220 nm (2-propanol:hexane=0.8:99.2), 1.0 mL/min;major enantiomer t_(major)=43.3 min, minor enantiomer t_(minor)=37.6min. [α]_(D) ²⁰=−21.1 (c=2.4, CHCl₃).

R_(f)=0.33 (EA:Hexane=1:4);

¹H NMR (100 MHz, CDCl₃) δ 9.75 (d, J=1.6 Hz, 0.85H) (syn isomer), 9.62(d, J=1.6 Hz, 0.15H) (anti isomer), 8.14-8.10 (m, 1H), 7.88 (d, J=8.0Hz, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.61-7.41 (m, 3H), 7.35 (d, J=7.1 Hz,1H), 4.94-4.76 (m, 3H), 3.01-2.96 (m, 1H), 1.21 (d, J=7.3 Hz, 0.45H)(anti isomer), 0.97 (d, J=7.3 Hz, 2.55H) (syn isomer);

¹³C NMR (100 MHz, CDCl₃) δ 202.5, 134.1, 133.3, 131.9, 129.2, 128.6,126.9, 126.0, 125.3, 123.9, 122.4, 77.9, 49.2, 37.4, 12.5;

IR (thin film) v/cm⁻¹: 3049, 2978, 2936, 1730, 1715, 1552, 1377, 1246,799, 779;

HRMS (ESI-TOF) Calcd. for C₁₅H₁₆NO₃: 258.1130 [M+H]⁺, Found: 258.1138[M+H]⁺.

(2S,3R)-2-isopropyl-4-nitro-3-phenylbutanal

The title compound was prepared from isovaleraldehyde and(E)-(2-nitrovinyl)benzene according to the general procedure. Theenantiomeric excess was determined by HPLC with an AD-H column at 210 nm(2-propanol:hexane=1:99), 1.0 mL/min; major enantiomer t_(major)=21.8min, minor enantiomer t_(minor)=17.9 min, the diastereomeric ratio wasdetermined by ¹H NMR. [α]_(D) ²⁰=−6.5 (c=2.3, CHCl₃).

R_(f)=0.38 (EA:Hexane=1:4);

¹H NMR (300 MHz, CDCl₃) δ=9.90 (d, J=2.4 Hz, 0.95H) (syn isomer), 9.48(d, J=2.4 Hz, 0.05H) (anti isomer), 7.36-7.28 (m, 3H), 7.27-7.18 (m,2H), 4.70-4.53 (m, 2H), 3.94-3.86 (m, 1H), 2.80-2.74 (m, 1H), 1.73-1.66(m, 1H), 1.08 (d, J=6.9 Hz, 2.1H) (syn isomer), 1.01 (d, J=6.9 Hz, 0.9H)(anti isomer), 0.92 (d, J=6.9 Hz, 0.9H) (anti isomer), 0.87 (d, J=6.9Hz, 2.1H) (syn isomer);

¹³C NMR (75 MHz, CDCl₃) δ 204.3, 137.0, 129.0, 128.3, 127.9, 78.9, 58.6,41.8, 27.8, 21.5, 16.8;

IR (neat) v/cm⁻¹ 2970, 2833, 2722, 1724, 1557, 1379, 1093, 816, 750,706, 648;

HRMS (ESI-TOF) Calcd. for C₁₃H₁₈NO₃: 236.1287 [M+H]⁺, Found: 236.1286[M+H]⁺.

(S)-2,2-dimethyl-4-nitro-3-phenyl butanal

The title compound was prepared from (E)-(2-nitrovinyl)benzene andisobutyraldehyde according to the general procedure. The enantiomericratio were determined by HPLC with Chiralpak OD-H column at 210 nm(2-propanol:hexane=15:85). 1 mL/min, t_(major)=19.7 min, t_(minor)=13.9min, [α]_(D) ²⁰=−4.3 (c=1.6, CHCl₃).

R_(f)=0.14 (EA:Hexane=1:10);

¹H NMR (300 MHz, CDCl₃) δ: 9.53 (s, 1H), 7.36-7.26 (m, 3H), 7.21-7.18(m, 2H), 4.85 (dd, J=12.9 Hz, 11.2 Hz, 1H), 4.68 (dd, J=12.9 Hz, 4.2 Hz,1H), 3.78 (dd, J=11.2 Hz, 4.2 Hz, 1H), 1.14 (s, 3H), 1.01 (s, 3H);

¹³C NMR (75 MHz, CDCl₃) δ: 204.2, 135.4, 129.1, 128.7, 128.2, 76.6,48.5, 48.2, 21.7, 18.9;

IR (thin film) v/cm⁻¹: 2922, 1728, 1556, 1454, 1379, 704;

HRMS (ESI-TOF) Calcd. for C₁₂H₁₆NO₃: 222.1130 [M+H]⁺, Found: 222.1123[M+H]⁺.

(S)-3-(4-bromophenyl)-2,2-dimethyl-4-nitrobutanal

The title compound was prepared fromtrans-1-bromo-4-(2-nitrovinyl)benzene and isobutyraldehyde according togeneral procedure. The enantiomeric excess was determined by HPLC withChiralpak AD-H column at 210 nm (2-propanol:hexane=10:90), 1 mL/min;t_(major)=11.5 min, t_(minor)=9.3 min, [α]_(D) ²⁰=−2.4 (c=2.9, CHCl₃);

R_(f)=0.24 (EA:Hexane=1:4);

¹H NMR (400 MHz, CDCl₃) δ: 9.49 (s, 1H), 7.46 (d, J=8.2 Hz, 2H), 7.08(d, J=8.2 Hz, 2H), 4.80 (t, J=12.9, 1H), 4.67 (dd, J=13.2, 4.2 Hz, 1H),3.75 (dd, J=11.4, 4.0 Hz, 1H), 1.12 (s, 3H), 1.00 (s, 3H);

¹³C NMR (100 MHz, CDCl₃) δ: 203.8, 134.5, 131.9, 130.7, 122.2, 76.0,48.1, 47.9, 21.7, 18.9;

IR (thin film) v/cm⁻¹: 2922, 2725, 1722, 1560, 1543, 1009, 880, 849,721;

HRMS (ESI-TOF) Calcd. for C₁₂H₁₅NO₃Br: 300.0235 [M+H]⁺, Found: 300.0212[M+H]⁺.

(S)-3-(furan-3-yl)-2,2-dimethyl-4-nitrobutanal

The title compound was prepared from trans-2-(2-nitrovinyl) furan, andisobutyraldehyde according to general procedure. The enantiomeric excesswas determined by HPLC with Chiralpak OD-H column at 210 nm(2-propanol:hexane=20:80), 1 mL/min, t_(major)=12.5 min, t_(minor)=8.3min, [α]_(D) ²⁰=+1.5 (c=2.8, CHCl₃);

R_(f)=0.33 (EA:Hexane=1:4);

¹H NMR (400 MHz, CDCl₃) δ: 9.52 (s, 1H,), 7.37 (s, 1H), 6.31 (dd, J=1.9,1.2 Hz, 1H), 6.21 (d, J=3.2 Hz, 1H), 4.75 (dd, J=12.9, 11.0 Hz, 1H),4.58 (dd, J=12.9 Hz, 3.9 Hz, 1H), 3.92 (dd, J=11.0 Hz, 3.9 Hz, 1H), 1.17(s, 3H), 1.04 (s, 3H);

¹³C NMR (100 MHz, CDCl₃) δ: 203.5, 149.8, 142.8, 110.4, 109.7, 74.9,48.2, 42.3, 21.2, 19.1;

IR (thin film) v/cm⁻¹: 2972, 1726, 1557, 1470, 1433, 1377, 1148, 885,818, 741;

HRMS (ESI-TOF) Calcd. for C₁₀H₁₄NO₄: 212.0923 [M+H]⁺, Found: 212.0926[M+H]⁺.

(S)-3-(4-Methoxyphenyl)-2,2-dimethyl-4-nitrobutanal

The title compound was prepared from trans-1-methoxy-4-(2-nitrovinyl)benzene and isobutyraldehyde according to general method. Theenantiomeric excess was determined by HPLC with Chiralpak AS-H column at210 nm (2-propanol:hexane=20:80), 1 mL/min; t_(major)=12.7 min,t_(minor)=15.8 min, [α]_(D) ²⁰=+9.1 (c=1.2, CHCl₃);

R_(f)=0.24 (EA:Hexane=1:4);

¹H NMR (400 MHz, CDCl₃) δ: 9.52 (s, 1H), 7.11 (d, J=8.6 Hz, 2H), 6.85(d, J=8.7 Hz, 2H), 4.80 (dd, J=12.8, 11.6 Hz, 1H), 4.66 (dd, J=12.8, 4.2Hz, 1H), 3.78 (s, 3H), 3.72 (dd, J=11.4, 4.2 Hz, 1H), 1.12 (s, 3H), 1.00(s, 3H),

¹³C NMR (100 MHz, CDCl₃) δ: 204.5, 159.3, 130.1, 127.1, 114.1, 76.5,55.2, 48.4, 47.9, 21.6, 18.9;

IR (thin film) v/cm⁻¹: 2922, 1719, 1609, 1549, 1514, 1462, 1377, 1250,1028, 839, 723;

HRMS (ESI-TOF) Calcd. for C₁₃H₁₈NO₄: 252.1236 [M+H]⁺, Found: 252.1239.

(S)-2,2-Dimethyl-3-(naphthalen-2-yl)-4-nitrobutanal

The title compound was prepared from (E)-2-(2-nitrovinyl)naphthalene andisobutyraldehyde according to General Procedure. The enantiomeric excesswas determined by HPLC with Chiralpak AS-H column at 210 nm(2-propanol:hexane=10:90), 1 mL/min, t_(major)=16.2 min, t_(minor)=18.0min, [α]_(D) ²⁰=+1.7 (c=1.8, CHCl₃)

R_(f)=0.27 (EA:Hexane=1:4);

¹H NMR (400 MHz, CDCl₃) δ: 9.57 (s, 1H), 7.83-7.80 (m, 3H), 7.67 (brs,1H), 7.50 (t, J=4.0 Hz, 2H), 7.32 (dd, J=8.5, 1.5 Hz, 1H), 4.99 (dd,J=13.0 Hz, 11.7 Hz, 1H), 4.78 (dd, J=13.2, 4.1 Hz, 1H), 3.96 (dd,J=11.3, 4.1 Hz, 1H), 1.19 (s, 3H), 1.05 (s, 3H);

¹³C NMR (100 MHz, CDCl₃) δ: 204.3, 133.1, 132.9, 128.5, 128.4, 127.9,127.8, 127.6, 126.6, 126.5, 126.4, 76.4, 48.6, 48.4, 21.8, 19.1;

IR (neat): 2725, 2670, 1722, 1555, 1306, 1159, 754, 721 cm⁻¹;

HRMS (ESI-TOF) Calcd. for C₁₆H₁₈NO₃: 272.1287 [M+H]⁺, Found: 272.1273.

(2S,3S)-2-methyl-3-(nitromethyl)-5-phenylpentanal

The title compound was prepared from (E)-(4-nitrobut-3-enyl)benzene andpropionaldehyde according to general procedure. The enantiomeric excesswas determined by HPLC with Chiralpak AD-H column at 210 nm(2-propanol:hexane=2:98), 1 mL/min, t_(major)=15.4 min, t_(minor)=14.4min, the diastereomeric ratio was determined by ¹H NMR. [α]_(D) ²⁰=−2.2(c=2.7, CHCl₃);

R_(f)=0.31 (EA:Hexane=1:4);

¹H NMR (400 MHz, CDCl₃): δ 9.64 (d, J=13.9 Hz, 0.43H) (anti isomer),9.61 (d, J=13.9 Hz, 0.57 H) (syn isomer), 7.32-7.14 (m, 5H), 4.56-4.51(m, 1H), 4.79-4.42 (m, 1H), 2.81-2.57 (m, 4H), 1.87 (m, 2H), 1.17 (d,J=17.2 Hz, 1.71H) (syn isomer), 0.95 (d, J=17.2 Hz, 1.29H) (antiisomer);

¹³C NMR (100 MHz, CDCl₃): δ 202.7, 140.5, 128.7, 128.2, 126.4, 47.0,36.8, 33.2, 30.3, 9.1;

IR (thin film) v/cm⁻¹: 3026, 2968, 2880, 1724, 1553, 1454, 700;

HRMS (ESI-TOF) Calcd. for C₁₃H₁₈NO₃: 236.1287 [M+H]⁺, Found: 236.1287[M+H]⁺.

(2S,3S)-3-cyclohexyl-2-methyl-4-nitrobutanal

The title compound was prepared from (E)-(2-nitrovinyl)cyclohexane andpropionaldehyde according to general procedure. The enantiomeric excesswas determined by HPLC with Chiralpak AD-H column at 210 nm(2-propanol:hexane=1:99), 1 mL/min, t_(major)=17.0 min, t_(minor)=19.1min, the diastereomeric ratio was determined by ¹H NMR. [α]_(D) ²⁰=−17.2(c=1.1, CHCl₃),

R_(f)=0.40 (EA:Hexane=1:4);

¹H NMR (500 MHz, CDCl₃): δ 9.68 (s, 1H) (anti isomer+syn isomer), 4.59(dd, J=5.3, 13.4 Hz, 1H), 4.38 (dd, J=6.8, 13.4 Hz, 1H), 2.61-2.54 (m,2H), 1.81-1.56 (m, 5H), 1.50-1.41 (m, 1H), 1.27-0.90 (m, 5H), 1.11 (d,J=7.0 Hz, 1.2H) (anti isomer), 1.20 (d, J=7.0 Hz, 1.8H) (syn isomer);

¹³C NMR (125 MHz, CDCl₃): δ 203.0, 75.2, 46.2, 43.5, 38.0, 31.6, 29.9,26.3, 26.3, 26.1, 9.9;

IR (neat): v/cm⁻¹: 2971, 2930, 2855, 1717, 1557, 1380, 1161, 1128, 950,816, 735.

HRMS (ESI-TOF): Calcd. for C₁₁H₂₀NO₃: 214.1443 [M+H]⁺, Found: 214.1446[M+H]⁺.

(2S,3R)-2-isopropyl-3-(naphthalen-1-yl)-4-nitrobutanal

The title compound was prepared from (E)-1-(2-nitrovinyl)naphthalene andisovaleraldehyde according to general procedure. The enantiomeric excesswas determined by HPLC with Chiralpak AD-H column at 254 nm(2-propanol:hexane=10:90), 1 mL/min, t_(major)=13.7 min, t_(minor)=16.8min, the diastereomeric ratio was determined by -major ¹H NMR. [α]_(D)²⁰=−178 (c=0.23, CHCl₃);

R_(f)=0.27 (EA:Hexane=1:4);

¹H NMR (300 MHz, CDCl₃): δ 10.0 (d, J=2.4 Hz, 0.96H) (syn isomer), 9.76(d, J=2.4 Hz, 0.04H) (anti isomer), 8.18 (brs, 1H), 7.85 (dd, J=24.0 Hz,7.5 Hz, 2H), 7.64-7.40 (m, 3H), 7.34 (d, J=7.5 Hz, 1H), 4.89-4.79 (m,2H), 3.09 (brs, 1H), 1.79 (s, 1H), 1.14 (d, J=6.9 Hz, 3H), 0.84 (d,J=6.9 Hz, 3H);

¹³C NMR (75 MHz, CDCl₃): δ 204.8, 134.3, 133.4, 131.7, 129.4, 128.6,126.9, 126.1, 125.4, 124.1, 122.3;

IR (neat) v/cm⁻¹ 3048, 2963, 2739, 1715, 1557, 1512, 1464, 799, 779,758;

HRMS (ESI-TOF) Calcd. for C₁₇H₂₀NO₃: 286.1443 [M+H]⁺, Found: 286.1441[M+H]⁺.

(2S,3R)-3-(4-bromophenyl)-2-isopropyl-4-nitrobutanal

The title compound was prepared from (E)-1-bromo-4-(2-nitrovinyl)benzeneand isovaleraldehyde according to general procedure. The enantiomericexcess was determined by HPLC with Chiralpak AD-H column at 254 nm(2-propanol:hexane=10:90), 1 mL/min, t_(major)=7.6 min, t_(minor)=7.2min, the diastereomeric ratio was determined by ¹H NMR. [α]_(D) ²⁰=−30.2(c=0.27, CHCl₃);

R_(f)=0.50 (EA:Hexane=1:4);

¹H NMR (400 MHz, CDCl₃) δ 9.91 (d, J=2.0 Hz, 0.98H) (syn isomer), 9.50(d, J=2.0 Hz, 0.02H) (anti isomer), 7.48 (d, J=8.4 Hz, 2H), 7.07 (d,J=8.4 Hz, 2H) 4.67 (dd, J=12.7 Hz, 4.3 Hz, 1H), 4.54 (dd, J=12.7 Hz, 4.3Hz, 1H), 3.88 (dt, J=10.5 Hz, 4.3 Hz, 1H), 2.75 (ddd, J=6.0 Hz, 3.8 Hz,2.1 Hz, 1H), 1.73-1.68 (m, 1H), 1.12 (d, J=7.2 Hz, 3H), 0.86 (d, J=7.2Hz, 3H);

¹³C NMR (100 MHz, CHCl₃) δ 203.9, 136.2, 132.4, 129.6, 122.1, 78.7,58.5, 41.4, 28.0, 21.6, 17.0;

IR (neat): v=2725, 1712 1566, 1338, 1261, 821, 719 cm^(—1);

HRMS (ESI-TOF) Calcd. for C₁₃H₁₇NO₃Br: 314.0392 [M+H]⁺, Found: 314.0384[M+H]⁺.

Characterization of Chiral Alcohol Obtained Using a Reduction ProcessAccording to the Invention

(R)-1-Phenylethanol (Coroley, E J, & Link, J O, Tetrahedron Lett. (1992)33, 4141)

(FIG. 11, entry 1): colorless oil, 98% yield, 81% ee, [α]_(D) ²⁵=−14.9(c=1.0, CH₂Cl₂);

R_(f)=0.41 (EA/Hexane=1/5);

¹H NMR (400 MHz, CDCl₃): δ 7.28-7.17 (m, 5H), 4.72 (q, J=6.5 Hz, 1H),3.23 (br, 1H), 1.37 (d, J=6.5 Hz, 3H);

¹³C NMR (100 MHz, CDCl₃): δ 145.7, 128.2, 127.1, 125.3, 70.0, 24.9;

The enantiomeric excess was determined by chiral HPLC analysis,employing a Dacicel Chiralcel OD column (Hexane:i-propanol 95:5, 1mL/min): t₁=8.66 min (major), t₂=10.33 min (minor).

(S)-2-Bromo-1-phenylethanol (Basavaiah, D, et al., Tetrahedron:Asymmetry (2002) 13, 1125-1128)

(FIG. 11, entry 2): colorless oil, 98% yield, 92% ee, [α]_(D) ²⁵=+55.3(c=0.5, CH₂Cl₂);

R_(f)=0.50 (EA/Hexane=1/4);

¹H NMR (300 MHz, CDCl₃): δ 7.38-7.32 (m, 5H), 4.92 (d, J=8.6 Hz, 1H),3.65-3.51 (m, 2H), 2.70 (br, 1H);

¹³C NMR (100 MHz, CDCl₃): δ 140.3, 128.7, 128.4, 125.9, 73.8, 40.2;

The enantiomeric excess was determined by chiral HPLC analysis,employing a Dacicel Chiralcel OD column (Hexane:i-propanol 95:5, 0.5mL/min): t₁=23.30 min (major), t₂=27.13 min (minor). FIG. 21 (A, B & C)depicts the data of HPLC analysis.

(R)-1-(4-Bromophenyl)-ethanol (Du, D-M., et al., Org. Lett. (2006) 8,1327-1330)

(not depicted in FIG. 11): colorless oil, 98% yield, 76% ee, [α]_(D)²⁵=+18.0 (c=3.0, CH₂Cl₂);

R_(f)=0.33 (EA/Hexane=1/4);

¹H NMR (400 MHz, CDCl₃): δ 7.47 (d, J=8.3 Hz, 2H), 7.25 (d, J=7.6 Hz,2H), 4.87 (q, J=3.7 Hz, 1H), 1.47 (d, J=6.4 Hz, 3H);

¹³C NMR (100 MHz, CDCl₃): δ 144.8, 131.6, 127.1, 121.2, 69.8, 25.2;

The enantiomeric excess determined by chiral HPLC analysis, employingchiral HPLC analysis, employing a Dacicel Chiralcel OB-H column(Hexane:i-propanol 95:5, 0.5 mL/min): t₁=7.57 min (minor), t₂=8.38 min(major). FIG. 22(A-D) depicts the data of HPLC analysis.

(R)-1-(2-Naphthyl)-ethanol (Josyula V, et al., Tetrahedron (2002) 58,1069-1074)

(FIG. 11, entry 3): colorless oil, 99% yield, 89% ee, [α]_(D) ²⁵=+21.9(c=2.2, CH₂Cl₂);

R_(f)=0.38 (EA/Hexane=1/4);

¹H NMR (400 MHz, CDCl₃): δ 7.77-7.71 (m, 4H), 7.44-7.41 (m, 3H), 4.95(q, J=6.4 Hz, 1H), 2.42 (brs, 1H), 1.50 (d, J=6.5 Hz, 3H);

¹³C NMR (100 MHz, CDCl₃): δ 143.1, 133.1, 132.7, 128.0, 127.8, 127.5,125.9, 125.5, 123.7, 123.6, 70.1, 24.9;

The enantiomeric excess was determined by chiral HPLC analysis,employing a Dacicel Chiralcel AS-H column (Hexane:i-propanol 97:3, 1mL/min), retention times (min): t₁=14.04 min (major), t₂=16.47 min(minor). FIG. 23(A-D) depicts the data of HPLC analysis.

(R)-1-(2-(2-(6-methoxy)-Naphthyl)-ethanol (Bouzemi, N, et al.,Tetrahedron: Asymmetry (2006) 17, 797-800)

(not depicted in FIG. 11): colorless solid, 98% yield, 70% ee, [α]_(D)²⁵=+26.7 (c=1.6, CH₂Cl₂);

R_(f)=0.32 (EA/hexane=1/4);

¹H NMR (300 MHz, CDCl₃): δ 7.68-7.65 (m, 3H), 7.42 (d, J=6.3 Hz, 1H),7.13-7.08 (m, 2H), 4.93 (q, J=4.4 Hz, 1H), 3.87 (s, 3H), 2.34 (br, 1H),1.51 (d, J=4.8 Hz, 3H);

¹³C NMR (75 MHz, CDCl₃): δ 157.5, 140.9, 133.9, 129.3, 128.6, 127.0,124.3, 123.7, 118.8, 105.6, 70.3, 55.2, 25.0;

The enantiomeric excess determined by chiral HPLC analysis, employing aDacicel Chiralcel OD column (Hexane:i-propanol 95:5, 1 mL/min): t₁=15.76min (minor), t₂=22.53 min (major). FIG. 24(A-D) depicts the data of HPLCanalysis.

(R)-1-(3-Trifluoromethylphenyl)-ethanol (Xu, Y, et al., J. Org. Chem.(2005) 70, 8079-8087)

(FIG. 11, entry 4): colorless oil, 98% yield. 86% ee, [α]_(D) ²⁵=+22.7(c=3.1, CH₂Cl₂);

R_(f)=0.28 (EA:hexane=1:4);

¹H NMR (400 MHz, CDCl₃): δ 7.61 (s, 1H), 7.50 (s, 2H), 7.43 (q, J=7.4Hz, 1H), 4.88 (br, 1H), 2.84 (br, 1H), 1.44 (d, J=6.3 Hz, 3H);

¹³C NMR (100 MHz, CDCl₃): δ 146.7, 130.7 (q, J=31.9 Hz), 128.9, 128.7,125.5, 124.1 (q, J=3.7 Hz), 122.1 (q, J=3.7 Hz), 69.7, 25.2.

The enantiomeric excess determined by HPLC analysis (Daicel ChiralcelOBH column, hexane:2-propanol=99:1 1.0 mL/min). Retention time:t_(minor)=5.47 and t_(major)=7.79 min. FIG. 29(A, B) and FIG. 30(A, B)depict the data of HPLC analysis.

(R)-1-(4-Nitrophenyl)-ethanol (Du, D-M., et al., Org. Lett. (2006) 8,1327-1330)

(FIG. 11, entry 6): colorless oil, 96% yield. 92% ee, [α]_(D) ²⁵=+26.7(c=1.6, CH₂Cl₂);

R_(f)=0.33 (EA/hexane=1/4);

¹H NMR (300 MHz, CDCl₃): δ 8.17 (d, J=8.7 Hz, 2H), 7.53 (d, J=8.7 Hz,2H), 5.01 (q, J=6.5 Hz, 1H), 1.51 (d, J=6.5 Hz, 3H);

¹³C NMR (75 MHz, CDCl₃): δ 153.2, 147.2, 126.1, 123.6, 69.4, 25.4;

The enantiomeric excess determined by HPLC analysis (Daicel Chiralcel_(tmajor) column, hexane:2-propanol=95:5, 1 mL/min). Retention time:t_(minor)=20.71 and t_(major)=21.48 min. FIG. 25(A, B) and FIG. 26(A, B)depict the data of HPLC analysis.

(R)-1-(3,4-difluorophenyl) ethanol (Burk, M. J, et al., Org. Lett.(2000) 2, 4173-4176; Dale, J A., et al. J. Org. Chem. (1969) 34,2543-2549)

(FIG. 11, entry 7): colorless solid, 99% yield. 95% ee, [α]_(D) ²⁵=+27.4(c=2.0, CH₂Cl₂);

R_(f)=0.26 (EA:hexane=1:4);

¹H NMR (300 MHz, CDCl₃): δ7.20-7.01 (m, 3H), 4.83-4.80 (m, J=6.5 Hz,1H), 2.53 (s, 1H), 1.43 (d, J=6.5 Hz, 3H);

¹³C NMR (75 MHz, CDCl₃): δ 151.5 (dd, J=12.4, 62.6 Hz), 148.2 (dd,J=12.4, 62.6 Hz), 142.8 (dd, J=4.9, 1.0 Hz), 121.2 (q, J=3.9 Hz), 117.0(d, J=17.0 Hz), 114.3 (d, J=17.0 Hz), 69.2, 25.2;

The enantiomeric excess determined by HPLC analysis (Daicel ChiralcelOB-H column, hexane:2-propanol=97:3 1.0 mL/min). Retention time:t_(minor)=7.73 and t_(major)=8.50 min. FIG. 34(A-D) depicts the data ofHPLC analysis.

(R)-1-(3,5-difluorophenyl) ethanol (Josyula V., et al., Tetrahedron(2002) 58, 1069-1074)

(FIG. 11, entry 8): colorless oil, 99% yield. 93% ee, [α]_(D) ²⁵=+34.8(c=1.3, CH₂Cl₂);

R_(f)=0.39 (EA:hexane=1:4);

¹H NMR (400 MHz, CDCl₃): δ 6.93-6.86 (m, 2H), 6.67-6.66 (m, 1H),4.92-4.84 (m, 1H), 1.90 (d, J=3.6 Hz, 1H), 1.48 (d, J=6.5 Hz, 3H);

¹³C NMR (100 MHz, CDCl₃): δ 164.8 (d, J=12.7 Hz), 161.5 (d, J=12.7 Hz),150.0 (t, J=8.3 Hz), 108.1 (d, J=25.5 Hz), 108.2 (d, J=8.9 Hz), 102.6(d, J=25.5 Hz), 69.5, 25.2;

The enantiomeric excess determined by HPLC analysis (Daicel ChiralcelOB-H column, hexane:2-propanol=97:3, 1.0 mL/min). Retention time:t_(minor)=6.50 and t_(major)=9.37 min. FIG. 32(A-D) depicts the data ofHPLC analysis.

(R)-1-(4-Trifluoromethylphenyl)-ethanol (Mathre D J., et al., J. Org.Chem. (1993) 58, 2880-2888)

(FIG. 11, entry 9): colorless oil, 99% yield. 97% ee, [α]_(D) ²⁵=+38.6(c=1.0, CH₂Cl₂);

R_(f)=0.39 (EA/hexane=1/4);

¹H NMR (300 MHz, CDCl₃): δ 7.53 (d, J=8.1 Hz, 2H), 7.36 (d, J=8.2 Hz,2H), 4.84-4.76 (m, 1H), 4.00 (d, J=3.6 Hz, 1H), 1.39 (d, J=6.5Hz, 3H);

¹³C NMR (75 MHz, CDCl₃): δ 149.1, 129.4 (q, J=32.0 Hz), 125.6, 125.2 (q,J=3.8 Hz), 122.4, 69.5, 25.0;

The enantiomeric excess determined by HPLC analysis (Daicel Chiralcel OJcolumn, hexane:2-propanol=99.8:0.2, 1.0 mL/min). Retention time:t_(major)=36.92 and t_(minor)=47.81 min. FIG. 28(A-D) depicts the dataof HPLC analysis.

(R)-3,5-bistrifluoromethylphenyl ethanol (Pollard, D, et al.,Tetrahedron: Asymmetry (2006) 17, 554-559)

(FIG. 11, entry 10): colorless solid, 99% yield. 93% ee, [α]_(D)²⁵=+15.0 (c=1.4, CH₂Cl₂);

R_(f)=0.48 (EA:hexane=1:4);

¹H NMR (400 MHz, CDCl₃): δ 7.84-7.77 (m, 3H), 5.02-5.00 (m, 1H),4.92-4.84 (m, 1H), 2.70 (d, J=3.6 Hz, 1H), 1.52 (d, J=6.5 Hz, 3H);

¹³C NMR (100 MHz, CDCl₃): δ 148.2, 131.7 (q, J=33.0 Hz), 150.0 (t, J=8.3Hz), 125.6 (d, J=2.5 Hz), 124.7, 122.0, 69.3, 25.4;

The enantiomeric excess determined by HPLC analysis (Daicel ChiralcelOB-H column, hexane:2-propanol=99.5:0.5, 1.0 mL/min). Retention time:t_(minor)=9.57 and t_(major)=10.34 min. FIG. 33(A-D) depicts the data ofHPLC analysis.

(R)-1-(3-fluorophenyl)-ethanol (Liu, P N., et al., Chem. Commun. (2004)2070-2071)

(FIG. 11, entry 11): colorless oil, 99% yield. 90% ee, [α]_(D) ²⁵=+17.8(c=0.9, CH₂Cl₂);

R_(f)=0.45 (EA/hexane=1/4);

¹H NMR (300 MHz, CDCl₃): δ 7.27-7.20 (m, 1H), 7.05-7.00 (m, 2H),6.93-6.87 (m, 1H), 4.76 (q, J=6.5 Hz, 3H), 3.4 (br, 1H), 1.38 (d, J=6.5Hz, 3H)

¹³C NMR (75 MHz, CDCl₃): δ 164.4, 161.2, 148.5 (d, J=6.6 Hz), 129.8 (d,J=8.3 Hz), 120.9 (d, J=2.8 Hz), 113.9 (d, J=22.1 Hz), 112.2 (d, J=22.1Hz), 69.4, 25.0.

The enantiomeric excess determined by HPLC analysis (Daicel ChiralcelOB-H column, hexane:2-propanol=99:1, 1 mL/min). Retention time:t_(minor)=17.58 and t_(major)=27.14 min.

(R)-1-(4-methylsulfonylphenyl) ethanol (Tagat, J R, et al., J. Med.Chem. (2001) 44, 3343-3346)

(not depicted in FIG. 11): colorless solid, 99% yield. 97% ee, [α]_(D)²⁵=+17.6 (c=0.6, CH₂Cl₂);

R_(f)=0.04 (EA:hexane=1:4);

¹H NMR (400 MHz, CDCl₃): 87.84 (d, J=8.3 Hz, 2H), 7.55 (d, J=8.3 Hz,2H), 4.98 (q, J=6.5 Hz, 1H), 3.03 (s, 3H), 1.49 (d, J=6.5 Hz, 3H);

¹³C NMR (100 MHz, CDCl₃): δ 152.4, 138.8, 127.3, 126.2, 69.2, 44.4,25.3;

The enantiomeric excess determined by HPLC analysis (Daicel ChiralcelOBH column, hexane:2-propanol=99:1 1.0 mL/min). Retention time:t_(minor)=60.93 and t_(major)=63.01 min. FIG. 31(A-D) depicts the dataof HPLC analysis.

X-Ray Crystal Data of 6a and 7a

Crystal Structure of 6a

The structure is graphically represented in FIG. 17.

chemical_formula_moiety C15 H18 N2 O4 chemical_formula_sum C15 H18 N2 O4chemical_formula_weight 290.31 symmetry_cell_setting Orthorhombicsymmetry_space_group_name_H-M P2(1)2(1)2(1) cell_length_a  7.9402(2)cell_length_b 11.7992(3) cell_length_c 15.7954(4) cell_angle_alpha 90.00cell_angle_beta 90.00 cell_angle_gamma 90.00 cell_volume 1479.84(6)cell_formula_units_Z 4 cell_measurement_temperature    296(2)cell_measurement_reflns_used 8324 cell_measurement_theta_min 2.58cell_measurement_theta_max 23.72 exptl_crystal_description fragmentexptl_crystal_colour colourless exptl_crystal_size_max 0.20exptl_crystal_size_mid 0.18 exptl_crystal_size_min 0.15exptl_crystal_density_meas 0 exptl_crystal_density_diffrn 1.303exptl_crystal_density_method ‘not measured’ exptl_crystal_F_000 616exptl_absorpt_coefficient_mu 0.095 exptl_absorpt_correction_typemulti-scan exptl_absorpt_correction_T_min 0.9812exptl_absorpt_correction_T_max 0.9858 exptl_absorpt_process_detailssadabs

Crystal Structure of 7a

The structure is graphically represented in FIG. 18.

Crystal data and structure refinement for 7a.

Identification code 7a Empirical formula C26 H26 N2 O3 Formula weight414.49 Temperature 173(2) K Wavelength 0.71073 Å Crystal systemMonoclinic Space group P2(1) Unit cell dimensions a = 11.7241(6) Å □ =90°. b = 5.6398(3) Å □ = 100.171(3)°. c = 16.4582(9) Å □ = 90°. Volume1071.14(10) Å³ Z 2 Density (calculated) 1.285 Mg/m³ Absorptioncoefficient 0.084 mm⁻¹ F(000) 440 Crystal size 0.25 × 0.08 × 0.04 mm³Theta range for data collection 1.76 to 27.99°. Index ranges −15 <= h <=15, −7 <= k <= 6, −21 <= l <= 21 Reflections collected 9241 Independentreflections 4937 [R(int) = 0.0399] Completeness to theta = 27.99° 100.0%Absorption correction Semi-empirical from equivalents Max. and min.transmission 0.9966 and 0.9792 Refinement method Full-matrixleast-squares on F² Data/restraints/parameters 4937/1/381Goodness-of-fit on F² 1.022 Final R indices [I>2sigma(I)] R1 = 0.0486,wR2 = 0.1034 R indices (all data) R1 = 0.0829, wR2 = 0.1271 Absolutestructure parameter −1.4(14) Largest diff. peak and hole 0.199 and−0.302 e.Å⁻³

X-Ray Crystal Data of(2S,3R)-3-(4-bromophenyl)-2-isopropyl-4-nitrobutanal

The structure is graphically represented in FIG. 16.

chemical_formula_moiety ‘C11 H12 Br N O3’ chemical_formula_sum ‘C11 H12Br N O3’ chemical_formula_weight 286.13 symmetry_cell_setting Monoclinicsymmetry_space_group_name_H-M P2(1) cell_length_a 10.6835(6)cell_length_b  8.7762(5) cell_length_c 12.7768(7) cell_angle_alpha 90.00cell_angle_beta  97.709(4) cell_angle_gamma 90.00 cell_volume 1187.13(12) cell_formula_units_Z 4 cell_measurement_temperature   173(2) cell_measurement_reflns_used 5754 cell_measurement_theta_min3.01 cell_measurement_theta_max 25.95 exptl_crystal_description plateexptl_crystal_colour colourless exptl_crystal_size_max 0.40exptl_crystal_size_mid 0.38 exptl_crystal_size_min 0.04exptl_crystal_density_diffrn 1.601 exptl_crystal_F_000 576exptl_absorpt_coefficient_mu 3.454 exptl_absorpt_correction_typemulti-scan exptl_absorpt_correction_T_min 0.3387exptl_absorpt_correction_T_max 0.8742 diffrn_ambient_temperature   173(2) diffrn_radiation_wavelength 0.71073 diffrn_radiation_typeMoK\a diffrn_radiation_source ‘fine-focus sealed tube’diffrn_radiation_monochromator graphite diffrn_measurement_device_type‘CCD area detector’ diffrn_reflns_number 23631diffrn_reflns_av_R_eguivalents 0.0520 diffrn_reflns_av_sigmaI/netI0.0645 diffrn_reflns_limit_h_min −14 diffrn_reflns_limit_h_max 15diffrn_reflns_limit_k_min −11 diffrn_reflns_limit_k_max 12diffrn_reflns_limit_l_min −18 diffrn_reflns_limit_l_max 18diffrn_reflns_theta_min 1.61 diffrn_reflns_theta_max 30.70reflns_number_total 6685 reflns_number_gt 4423reflns_threshold_expression >2sigma(I)

Computational Details

DFT calculations were carried out with the Gaussian 03 package (Frisch,M J, et al., Gaussian 03, Revision D.01, Gaussian, Inc.: Wallingford,Conn., 2004). The structures are fully optimized by the B3LYP (Becke, AD J, Chem. Phys. (1993) 98, 1372; Becke, A D J, Chem. Phys. (1993) 98,5648; Lee, C, et al, Phys. Rev. B (1988) 37, 785) method using 6-31G(d)basis set (Ditchfield, R, et al., J. Chem. Phys. (1971) 54, 724) andhave been confirmed to be a local minima by the harmonic frequenciescalculations at the same level of theory.

Computational Results and Discussions

Different conformers of the enamine intermediate have been calculated todetermine the lowest energy conformation in the gas phase. The lowestenergy conformation syn enamine 2 is displayed in FIG. 9A. In thisconformation, there is hydrogen bond between OH group and the nitrogenatom and the bond distance for N—H is 2.057 Å. The hydrogen bondinginteraction can enhance the stability of this conformer, as its energyis 2.63 kJ/mol lower than that of the second lowest conformation synenamine 1. From this conformer, we can see that, at the Si surface ofenamine, there are several highly electronegative atoms such as O and Nwhich could function as hydrogen bond acceptors. Therefore when theenamine is immersed into protic solvents such as methanol and water, theSi face is expected to develop strong hydrogen-bond networks whicheventually block the attack of nitrostyrene from this side. On thisbasis, nitrostyrene will attack the enamine from the less hindered Reface via transition state TS1, where a water molecule is probablyinvolved by forming hydrogen bonds with the CO₂H group and NO₂ whichwill lead to the desired (S, R) product (FIG. 9B). The activation energyof this TS model is 64.61 kJ/mol lower than that of TS2 without thewater molecule as hydrogen-bond bridge. The whole system is stabilizedby hydrogen bonds. This proposal is supported by the followingexperimental results: (1) methyl ester derivative or phenyl esterderivative could not catalyze the reaction with or without acid additivein MeOH or H₂O, which indicate the possible activation of nitrostyreneby the carboxylic acid. (2) the reaction was much slower in aproticsolvent such DMSO and DMF which implies that H₂O may be involved in thereaction through hydrogen-bonding interaction. The transition state TS3,proposed for similar reaction (Seebach' model), (12. (a) Seebach, D.;Golinski, J. Helv. Chim. Acta 1981, 64, 1413. (Seebach, D, et al., Helv.Chim. Acta (1985), 68, 162) is found 7.91 kJ/mol higher than the energyof TS1 by DFT calculation.

syn enamine 1 (depicted in FIG. 35A) C 2.317253 0.425596 −0.079496 C2.482760 −0.782657 −0.774622 C 0.177617 −0.103916 −1.002930 C 1.130027−1.315288 −1.159221 H −0.005180 0.436744 −1.937684 H 1.077889 −1.720655−2.174576 N 0.952011 0.802790 −0.089580 C 0.568993 −2.333302 −0.131202 H0.764459 −3.371314 −0.411303 H 1.028580 −2.149221 0.844347 C −0.943794−2.028180 −0.068650 H −1.510268 −2.681807 −0.747207 N −1.061177−0.643278 −0.497498 C 0.492883 2.001811 0.406920 O 1.126763 2.7517281.127752 O −0.768850 2.252880 −0.017319 C −1.371410 3.442707 0.542389 H−0.759845 4.309026 0.271967 H −1.363987 3.357552 1.633156 C −1.473021−2.241356 1.350543 O −1.329398 −1.486065 2.280887 O −2.099755 −3.4419251.458277 H −2.364509 −3.525762 2.394146 C 3.744500 −1.337503 −0.938972 H3.867611 −2.272731 −1.480055 C 3.412057 1.086604 0.479991 H 3.2765562.010448 1.024591 C 4.677937 0.515894 0.304791 H 5.541540 1.0224990.727633 C 4.854477 −0.676578 −0.399507 H 5.849422 −1.093776 −0.525535 C−2.781415 3.546591 −0.007206 H −3.371593 2.665501 0.262492 H −3.2725294.433767 0.407373 H −2.773236 3.640422 −1.098532 C −2.293367 −0.175218−0.956346 H −2.225026 0.783705 −1.459146 C −3.485367 −0.778505 −0.816625H −3.570382 −1.722802 −0.282755 C −4.764046 −0.198970 −1.355784 H−4.586872 0.752558 −1.870444 H −5.248447 −0.877181 −2.072387 H −5.496611−0.012878 −0.557742 SCF Energy = −1070.27086981 Zero-point correction(ZPE) = 0.354393 syn enamine 2 (depicted in FIG. 9A) C 2.314188 0.417552−0.076147 C 2.461103 −0.798361 −0.759337 C 0.153576 −0.119009 −0.938252C 1.101578 −1.332159 −1.117841 H −0.068211 0.405778 −1.872800 H 1.030547−1.729786 −2.135253 N 0.943816 0.796928 −0.059363 C 0.558558 −2.359161−0.093222 H 0.770182 −3.394906 −0.366770 H 1.012133 −2.171863 0.885775 C−0.954832 −2.080867 −0.046814 H −1.488241 −2.688373 −0.789359 N−1.080124 −0.649709 −0.362338 C 0.509739 2.031141 0.374963 O 1.1761652.826071 1.011664 O −0.779136 2.248363 0.012659 C −1.337184 3.5027650.476468 H −0.728275 4.323493 0.086031 H −1.271455 3.530887 1.568266 C−1.536977 −2.428331 1.330912 O −1.598476 −1.391404 2.187609 O −1.861314−3.550191 1.636378 C 3.717684 −1.361845 −0.936138 H 3.828119 −2.304081−1.467230 C 3.418881 1.081371 0.458293 H 3.297971 2.014504 0.990036 C4.679292 0.502411 0.270335 H 5.551783 1.010060 0.672683 C 4.838195−0.699692 −0.421452 H 5.828863 −1.123634 −0.557245 C −2.772487 3.576740−0.007864 H −3.362318 2.739511 0.378002 H −3.228270 4.509480 0.341388 H−2.821538 3.562785 −1.101860 C −2.313514 −0.209307 −0.894727 H −2.2549300.776286 −1.343283 C −3.482968 −0.862080 −0.841158 H −3.556274 −1.834437−0.358753 C −4.758869 −0.303071 −1.406641 H −5.184869 −0.967501−2.170529 H −5.526364 −0.186513 −0.629469 H −4.599300 0.677541 −1.869123H −1.349079 −0.591069 1.676648 SCF Energy = −1070.27180798 Zero-pointcorrection (ZPE) = 0.354653 syn enamine 3 (depicted in FIG. 36) C2.300297 0.288398 −0.031250 C 2.397101 −0.931742 −0.716751 C 0.162490−0.086417 −1.020038 C 1.022151 −1.366444 −1.147072 H 0.052144 0.459574−1.961749 H 0.975885 −1.760770 −2.167013 N 0.959859 0.759896 −0.078041 C0.353663 −2.343823 −0.148450 H 0.454455 −3.390831 −0.441624 H 0.819397−2.233664 0.835879 C −1.131260 −1.914370 −0.097375 H −1.740537 −2.536746−0.760876 N −1.150164 −0.512483 −0.547027 C 0.585706 2.018675 0.344100 O1.269563 2.767495 1.016607 O −0.669927 2.312187 −0.075577 C −1.1831633.592616 0.367894 H −0.478483 4.375683 0.074063 H −1.236492 3.5859071.461123 C −1.668578 −2.079856 1.332984 O −1.731399 −0.940046 2.043809 O−1.966201 −3.157081 1.791685 C 3.619346 −1.579355 −0.835379 H 3.691854−2.524443 −1.367927 C 3.419342 0.872284 0.562637 H 3.335497 1.8087721.095755 C 4.645033 0.208865 0.432632 H 5.529103 0.653123 0.881931 C4.755394 −0.997957 −0.260330 H 5.720262 −1.488391 −0.350355 C −2.5480203.781913 −0.266272 H −3.224658 2.966060 0.005973 H −2.984415 4.7255420.078413 H −2.472583 3.819138 −1.358140 C −2.279621 0.012286 −1.217888 H−2.016719 0.890112 −1.797670 C −3.572006 −0.356068 −1.222482 H −1.485272−0.214161 1.429112 C −4.353595 −1.431432 −0.515466 H −3.770589 −2.0960360.121348 H −5.127895 −0.976542 0.117361 H −4.882749 −2.060146 −1.244411H −4.188039 0.280060 −1.856861 SCF Energy = −1070.26482028 Zero-pointcorrection (ZPE) = 0.354984 anti enamine 4 (depicted in FIG. 37) C−2.192429 0.634856 0.193907 C −2.555215 −0.650648 0.628111 C −0.200796−0.385911 0.998100 C −1.307128 −1.455009 0.869396 H −0.047688 −0.0326392.022214 H −1.343349 −2.074668 1.770913 N −0.775431 0.755817 0.192507 C−0.826000 −2.285030 −0.351221 H −1.162823 −3.323097 −0.321463 H−1.212541 −1.840252 −1.273244 C 0.721476 −2.188344 −0.306259 H 1.155860−3.089029 0.144592 N 1.003117 −1.007748 0.519215 C −0.107826 1.829889−0.346729 O −0.634388 2.826654 −0.804940 O 1.239361 1.626537 −0.346674 C2.028756 2.721119 −0.884944 H 1.944242 3.573232 −0.202802 H 1.6037543.017231 −1.846990 C 1.314693 −2.070038 −1.721235 O 1.697837 −0.831436−2.082401 O 1.396508 −3.020224 −2.461975 C −3.891801 −1.010680 0.728280H −4.169284 −2.006060 1.066268 C −3.160663 1.575608 −0.156605 H−2.875230 2.562026 −0.493561 C −4.504464 1.196741 −0.052622 H −5.2721231.919257 −0.316301 C −4.875628 −0.074769 0.387364 H −5.926169 −0.3391710.465586 C 3.458615 2.231752 −1.014868 H 3.524106 1.391117 −1.713312 H4.087870 3.043234 −1.396258 H 3.854399 1.908902 −0.047250 C 2.199818−0.966385 1.255071 H 2.839494 −1.825742 1.059436 C 2.602395 −0.0223032.117328 H 1.991195 0.862317 2.281091 C 3.888307 −0.111123 2.890971 H4.536735 0.754584 2.698619 H 3.709503 −0.133010 3.974931 H 4.452518−1.013832 2.630948 H 1.568531 −0.221477 −1.321825 SCF Energy =−1070.26865670 Zero-point correction (ZPE) = 0.354347 anti enamine 5(depicted in FIG. 38) C 2.099727 −0.654681 −0.012732 C 2.536948 0.5732970.510388 C 0.217604 0.327665 1.059606 C 1.337820 1.379948 0.927510 H0.163737 −0.124317 2.051434 H 1.467452 1.918284 1.871637 N 0.682665−0.739427 0.088894 C 0.773414 2.319047 −0.170947 H 1.149920 3.341109−0.097433 H 1.049140 1.935623 −1.158154 C −0.763025 2.264341 0.024634 H−1.110842 3.126713 0.606019 N −1.008378 1.013932 0.760883 C −0.060293−1.692560 −0.566730 O 0.397929 −2.628929 −1.194055 O −1.398290 −1.447472−0.462813 C −2.257529 −2.433267 −1.099351 H −2.137742 −3.383797−0.570422 H −1.920470 −2.575327 −2.129009 C −1.498268 2.316899 −1.324989O −1.940489 1.134032 −1.788148 O −1.632557 3.348606 −1.938285 C 3.8883020.888320 0.535840 H 4.223936 1.839423 0.941679 C 3.006241 −1.582133−0.525553 H 2.663019 −2.523019 −0.931697 C 4.365783 −1.249017 −0.495522H 5.086665 −1.961677 −0.887021 C 4.811094 −0.035060 0.030004 H 5.8725920.194359 0.046962 C −3.680108 −1.911440 −1.027012 H −3.782342 −0.971336−1.578379 H −4.359108 −2.645699 −1.473933 H −3.986265 −1.740310 0.009558C −2.150239 0.949516 1.578062 H −2.769410 1.834945 1.451437 C −2.5856630.013850 2.439405 H −1.754232 0.432382 −1.123987 C −2.015105 −1.3232522.832901 H −1.335532 −1.738616 2.086280 H −1.478520 −1.275759 3.791725 H−2.826292 −2.048788 2.970584 H −3.508681 0.285531 2.947598 SCF Energy =−1070.26332004 Zero-point correction (ZPE) = 0.354781 Model TS1 (withwater) (depicted in FIG. 9B) C −3.530557 −0.930491 −0.024005 C −3.6415840.156346 −0.895862 C −1.389808 −0.662939 −0.992193 C −2.360622 0.335682−1.683965 H −0.801807 −1.280570 −1.669984 H −2.508445 0.065921 −2.736258N −2.238684 −1.513092 −0.156987 C −1.687472 1.717208 −1.565429 H−1.041525 1.902895 −2.430032 H −2.416888 2.528429 −1.509077 C −0.8226071.634052 −0.294196 H 0.090224 2.228630 −0.413776 N −0.463419 0.213481−0.220329 C −1.930398 −2.798911 0.231840 O −2.668076 −3.533808 0.856475O −0.680215 −3.148961 −0.181575 C −0.285801 −4.503943 0.159050 H−1.085203 −5.184832 −0.143601 H −0.182872 −4.572170 1.246617 C −1.5496412.093889 0.994999 O −1.780605 3.402070 1.058134 O −1.886718 1.3205361.862375 C −4.821568 0.886771 −0.956035 H −4.915180 1.733397 −1.631871 C−4.580800 −1.313851 0.805441 H −4.480326 −2.157782 1.473349 C −5.762710−0.569401 0.735063 H −6.595342 −0.846162 1.375604 C −5.889651 0.518552−0.131410 H −6.816800 1.083022 −0.163068 C 1.017213 −4.797742 −0.558316H 1.807903 −4.102733 −0.258502 H 1.345257 −5.814149 −0.315142 H 0.889102−4.730644 −1.643850 C 0.537454 −0.253984 0.512965 H 0.646166 −1.3355060.497175 C 1.518182 0.539617 1.166082 H 1.220533 1.574015 1.311516 C2.163903 −0.055524 2.404304 H 3.051597 0.522448 2.682642 H 1.468067−0.022111 3.250258 H 2.469149 −1.095772 2.251856 C 2.885227 0.848207−0.160240 H 2.238174 0.935718 −1.029391 C 3.489245 2.101645 0.164858 H4.374794 2.235015 0.767251 C 3.753975 −0.368785 −0.219716 C 3.433794−1.388637 −1.130061 C 4.894515 −0.534987 0.582380 C 4.224143 −2.532429−1.242426 H 2.563272 −1.272013 −1.772384 C 5.683078 −1.680698 0.477741 H5.177239 0.236734 1.291285 C 5.352420 −2.684423 −0.434033 H 3.964948−3.298448 −1.968482 H 6.562548 −1.785124 1.107320 H 5.972056 −3.572760−0.519625 N 2.873390 3.269415 −0.174775 O 3.354701 4.371800 0.152653 O1.772499 3.208719 −0.859789 O −0.268968 4.891668 −0.537413 H 0.6332344.479429 −0.626073 H −0.503244 5.189833 −1.427690 H −1.266161 3.9391270.380667 SCF Energy = −1660.83606625 Zero-point correction (ZPE) =0.519253 Model TS2 (without water) (depicted in FIG. 9C) C 3.5701250.580467 0.115314 C 3.681044 −0.424125 −0.849212 C 1.496426 0.533271−1.008117 C 2.459555 −0.429894 −1.744904 H 0.970982 1.240604 −1.648872 H2.713502 −0.031351 −2.734641 N 2.321355 1.252589 −0.042544 C 1.695279−1.760828 −1.893377 H 1.187042 −1.795276 −2.862123 H 2.367678 −2.620326−1.842561 C 0.640990 −1.791756 −0.765430 H −0.322884 −2.148365 −1.130262N 0.492416 −0.373527 −0.372957 C 2.070611 2.531676 0.409623 O 2.8090323.173597 1.128150 O 0.871184 2.983699 −0.051143 C 0.529791 4.3357910.353309 H 1.384054 4.985939 0.148803 H 0.356645 4.340770 1.434108 C1.085914 −2.673895 0.432958 O 0.356366 −3.767348 0.644511 O 2.058222−2.392229 1.095526 C 4.821270 −1.213809 −0.905171 H 4.917043 −1.997150−1.652940 C 4.576225 0.820048 1.046419 H 4.476846 1.605135 1.783274 C5.717509 0.014184 0.981613 H 6.517158 0.177828 1.698502 C 5.844966−0.991869 0.021323 H 6.739692 −1.606753 −0.004974 C −0.704072 4.748302−0.425404 H −1.545789 4.076466 −0.229677 H −0.998575 5.761534 −0.131430H −0.504024 4.749673 −1.502035 C −0.438579 0.068928 0.462330 H −0.4354811.145512 0.613078 C −1.456003 −0.727920 1.057093 H −1.199419 −1.7818771.100733 C −2.028676 −0.212623 2.366564 H −2.930009 −0.777926 2.626593 H−1.310616 −0.345501 3.183598 H −2.293939 0.848442 2.312795 C −2.866891−0.911554 −0.201495 H −2.262131 −1.062334 −1.092560 C −3.577766−2.097652 0.170540 H −4.486472 −2.119511 0.752556 C −3.629035 0.377046−0.260872 C −3.266986 1.337197 −1.219040 C −4.702101 0.671022 0.595404 C−3.953019 2.546778 −1.325682 H −2.447346 1.122727 −1.901840 C −5.3873151.882072 0.495047 H −5.011214 −0.050303 1.345021 C −5.016516 2.825292−0.464525 H −3.664984 3.265392 −2.088440 H −6.217089 2.085400 1.166502 H−5.555876 3.764898 −0.546089 N −3.036080 −3.329301 −0.052002 O −3.600601−4.361274 0.353277 O −1.914866 −3.401182 −0.708667 H −0.499792 −3.7809810.116326 SCF Energy = −1584.39884194 Zero-point correction (ZPE) =0.494339 Model TS3 (with water) (depicted in FIG. 39) C −3.7282750.185967 −0.411241 C −3.604276 −1.030849 0.269226 C −1.752290 0.3501250.859136 C −2.477901 −0.947405 1.279668 H −1.387288 0.961473 1.683537 H−2.880350 −0.848539 2.294921 N −2.716098 1.081181 0.038131 C −1.398138−2.036392 1.240288 H −0.852501 −2.056952 2.187197 H −1.807269 −3.0314281.049810 C −0.417977 −1.593893 0.127997 H 0.598813 −1.823659 0.424702 N−0.574749 −0.134342 0.083194 C −2.774575 2.450515 −0.096539 O −3.6406993.057493 −0.694833 O −1.722587 3.046290 0.529212 C −1.734205 4.4950080.499644 H −2.658419 4.845136 0.968901 H −1.744210 4.825528 −0.543191 C−0.654695 −2.296632 −1.217698 O −0.237745 −3.574331 −1.198530 O−1.153707 −1.781509 −2.187566 C −4.482490 −2.072360 0.000167 H −4.394923−3.019763 0.526417 C −4.719584 0.394853 −1.365868 H −4.807692 1.344211−1.876093 C −5.594868 −0.664371 −1.628275 H −6.374922 −0.528602−2.372272 C −5.482575 −1.885719 −0.960378 H −6.172177 −2.693616−1.186853 C −0.502600 4.974669 1.243405 H 0.415074 4.632318 0.753541 H−0.489849 6.069708 1.263738 H −0.499258 4.609880 2.275212 C 0.3502450.715349 −0.343141 H 0.089127 1.757492 −0.176622 C 1.589642 0.435761−0.963567 H 1.711008 −0.575654 −1.346411 C 2.071713 1.520822 −1.916412 H3.098342 1.338561 −2.239853 H 1.442017 1.558874 −2.814053 H 2.0380442.510931 −1.444557 C 2.976097 0.323514 0.553391 H 2.722679 1.2736831.014120 C 2.710309 −0.805756 1.367179 H 3.135568 −1.783407 1.193793 C4.261610 0.328371 −0.197335 C 5.056924 1.484994 −0.196827 C 4.724492−0.801437 −0.893618 C 6.286928 1.508865 −0.854320 H 4.711734 2.3677310.335718 C 5.949410 −0.776010 −1.556408 H 4.119539 −1.703782 −0.924068 C6.737077 0.378362 −1.537157 H 6.891516 2.411516 −0.833542 H 6.290022−1.658751 −2.090603 H 7.692519 0.395973 −2.054089 N 1.728532 −0.7707722.310672 O 1.387846 −1.873496 2.880794 O 1.146103 0.309098 2.600668 O1.315154 −3.976145 1.085126 H 1.387040 −3.285225 1.796565 H 1.303581−4.826567 1.547569 H 0.263541 −3.776861 −0.364382 SCF Energy =−1660.83004325 Zero-point correction (ZPE) = 0.518898 Water O −0.0242480.000000 −0.017137 H 0.025062 0.000000 0.950263 H 0.904123 0.000000−0.293580 SCF Energy = −76.4089533236 Zero-point correction (ZPE) =0.021168

In summary, a new class of structurally rigid tricyclic amphibian chiralcatalysts based on the hexahydropyrrolo[2,3-b]indole skeleton has beendeveloped. The special features of this catalyst include: (1) easilyprepared in large scale; (2) 10/DMAP catalyst has been shown to affordthe desired products in high yields and excellent enantioselectivitiesin the Michael addition of aldehydes to nitroalkenes both in organicsolvents and in water; (3) only slight excess of aldehyde is used inthis system; (4) low catalyst loading and broad substrate scope.Efficient enamine control has been shown and withoutr being bound bytheory evidence points to the involvement of a chiral pocket. Further,Ligand 7a has been used for the asymmetric reduction of ketones toafford the desired product in excellent yield and highenantioselectivities. These advantages render these chiral catalysteparticularly suitable for practical use and will certainly findapplication in asymmetric synthesis. The success of this novel catalystdesign will open up new perspectives in chiral catalyst or liganddesign. Further applications to other asymmetric reactions using thisnew catalyst or using this skeleton as chiral ligand as well asmechanistic insight are ongoing in our group. These advantages furtherrender the chiral 10/DMAP catalyst more competitive than proline andmore suitable for practical use, thus it will certainly find wideapplication in organocatalysis. Finally, the success of this novelcatalyst design clarifies that it is inefficient enamine control due toproline's skeleton and not the hydrogen bonding intereaction which isresponsible for the failure of poor hydrogen bond acceptors to serve aselectrophiles.

The invention has been described broadly and generically herein. Each ofthe narrower species and subgeneric groupings falling within the genericdisclosure also form part of the invention. This includes the genericdescription of the invention with a proviso or negative limitationremoving any subject matter from the genus, regardless of whether or notthe excised material is specifically recited herein. Other embodimentsare within the following claims. In addition, where features or aspectsof the invention are described in terms of Markush groups, those skilledin the art will recognize that the invention is also thereby describedin terms of any individual member or subgroup of members of the Markushgroup.

One skilled in the art would readily appreciate that the presentinvention is well adapted to carry out the objects and obtain the endsand advantages mentioned, as well as those inherent therein. Further, itwill be readily apparent to one skilled in the art that varyingsubstitutions and modifications may be made to the invention disclosedherein without departing from the scope and spirit of the invention. Thecompositions, methods, procedures, treatments, molecules and specificcompounds described herein are presently representative of preferredembodiments are exemplary and are not intended as limitations on thescope of the invention. Changes therein and other uses will occur tothose skilled in the art which are encompassed within the spirit of theinvention are defined by the scope of the claims. The listing ordiscussion of a previously published document in this specificationshould not necessarily be taken as an acknowledgement that the documentis part of the state of the art or is common general knowledge.

The invention illustratively described herein may suitably be practicedin the absence of any element or elements, limitation or limitations,not specifically disclosed herein. Thus, for example, the terms“comprising”, “including,” containing”, etc. shall be read expansivelyand without limitation. The word “comprise” or variations such as“comprises” or “comprising” will accordingly be understood to imply theinclusion of a stated integer or groups of integers but not theexclusion of any other integer or group of integers. Additionally, theterms and expressions employed herein have been used as terms ofdescription and not of limitation, and there is no intention in the useof such terms and expressions of excluding any equivalents of thefeatures shown and described or portions thereof, but it is recognizedthat various modifications are possible within the scope of theinvention claimed. Thus, it should be understood that although thepresent invention has been specifically disclosed by exemplaryembodiments and optional features, modification and variation of theinventions embodied therein herein disclosed may be resorted to by thoseskilled in the art, and that such modifications and variations areconsidered to be within the scope of this invention.

Further Embodiments

-   1. A hexahydropyrrolo[2,3-b] indole compound of Formula (XX)

-   -   wherein    -   R is one of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³, —R⁴CONR⁵R⁶,        —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂), —R⁴C(O)C(R³)CR⁵R⁶ and        —R⁴CO₂COR³, and R³¹ is one of hydrogen, —COOR³, —R⁴COOR³,        —R⁴CHO, —R⁴COR³, —R⁴CONR⁵R⁶, —R⁴COX, —R⁴OP(═O)(OH)₂,        —R⁴P(═O)(OH)₂), —R⁴C(O)C(R³)CR⁵R⁶ and —R⁴CO₂C(R³)O,        -   wherein R³, R⁵ and R⁶ are independent from one another one            of hydrogen, an aliphatic group with a main chain having 1            to about 20 carbon atoms, an alicyclic group, an aromatic            group, an arylaliphatic group and an arylalicyclic group,            comprising 0 to about 3 heteroatoms independently selected            from the group consisting of N, O, S, Se and Si,        -   R⁴ is one of an aliphatic bridge with a main chain having 1            to about 20 carbon atoms, an alicyclic bridge, an aromatic            bridge, an arylaliphatic bridge and an arylalicyclic bridge,            comprising 0 to about 3 heteroatoms independently selected            from the group consisting of N, O, S, Se and Si,        -   X is halogen, and    -   R³⁰ is one of —C(OH)R¹R² and —COOR¹⁴, wherein R¹, R² and R¹⁴ are        independent from one another one of hydrogen, an aliphatic group        with a main chain having 1 to about 20 carbon atoms, an        alicyclic group, an aromatic group, an arylaliphatic group and        an arylalicyclic group, comprising 0 to about 3 heteroatoms        independently selected from the group consisting of N, O, S, Se        and Si.

-   2. The compound of clause 1, wherein R³⁰ is —COOR¹⁴, R¹⁴ being alkyl    or a protecting group that is removable in the presence of R by    hydrogenolysisl.

-   3. A hexahydropyrrolo[2,3-b]indole compound of Formula (VII)

-   -   wherein    -   R is one of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³, —R⁴CONR⁵R⁶,        —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂), —R⁴C(O)C(R³)CR⁵R⁶ and        —R⁴CO₂C(R³)O, wherein R³, R⁵ and R⁶ are independent from one        another one of hydrogen, an aliphatic group with a main chain        having 1 to about 20 carbon atoms, an alicyclic group, an        aromatic group, an arylaliphatic group and an arylalicyclic        group, comprising 0 to about 3 heteroatoms independently        selected from the group consisting of N, O, S, Se and Si, R⁴ is        one of an aliphatic bridge with a main chain having 1 to about        20 carbon atoms, an alicyclic bridge, an aromatic bridge, an        arylaliphatic bridge and an arylalicyclic bridge, comprising 0        to about 3 heteroatoms independently selected from the group        consisting of N, O, S, Se and Si, X is halogen, and

R¹ and R² are independent from one another one of hydrogen, an aliphaticgroup with a main chain having 1 to about 20 carbon atoms, an alicyclicgroup, an aromatic group, an arylaliphatic group and an arylalicyclicgroup, comprising 0 to about 3 heteroatoms independently selected fromthe group consisting of N, O, S, Se and Si.

-   4. The compound of clause 3 wherein R¹ and R² are identical.-   5. A compound of Formula (VIII)

-   -   the compound having a bowl-shaped conformation,    -   wherein M is a metal selected from the group consisting of Group        1 to Group 14 metals, lanthanides and actinides,    -   wherein R is one of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³,        —R⁴CONR⁵R⁶, —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂),        —R⁴C(O)C(R³)CR⁵R⁶ and R⁴CO₂C(R³)O, wherein R³, R⁵ and R⁶ are        independent from one another one of hydrogen, an aliphatic group        with a main chain having 1 to about 20 carbon atoms, an        alicyclic group, an aromatic group, an arylaliphatic group and        an arylalicyclic group, comprising 0 to about 3 heteroatoms        independently selected from the group consisting of N, O, S, Se        and Si, R⁴ is one of an aliphatic bridge with a main chain        having 1 to about 20 carbon atoms, an alicyclic bridge, an        aromatic bridge, an arylaliphatic bridge and an arylalicyclic        bridge, comprising 0 to about 3 heteroatoms independently        selected from the group consisting of N, O, S, Se and Si, X is        halogen, and    -   R¹ and R² are independent from one another one of hydrogen, an        aliphatic group with a main chain having 1 to about 20 carbon        atoms, an alicyclic group, an aromatic group, an arylaliphatic        group and an arylalicyclic group, comprising 0 to about 3        heteroatoms independently selected from the group consisting of        N, O, S, Se and Si.

-   6. A compound of Formula (IX)

-   -   the compound having an S-shaped conformation,    -   wherein M is a metal selected from the group consisting of Group        1 to Group 14 metals, lanthanides and actinides,    -   R is one of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³, —R⁴CONR⁵R⁶,        —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂), —R⁴C(O)C(R³)CR⁵R⁶ and        —R⁴CO₂C(R³)O, wherein R³, R⁵ and R⁶ are independent from one        another one of hydrogen, an aliphatic group with a main chain        having 1 to about 20 carbon atoms, an alicyclic group, an        aromatic group, an arylaliphatic group and an arylalicyclic        group, comprising 0 to about 3 heteroatoms independently        selected from the group consisting of N, O, S, Se and Si, R⁴ is        one of an aliphatic bridge with a main chain having 1 to about        20 carbon atoms, an alicyclic bridge, an aromatic bridge, an        arylaliphatic bridge and an arylalicyclic bridge, comprising 0        to about 3 heteroatoms independently selected from the group        consisting of N, O, S, Se and Si, X is halogen, and    -   R¹ and R² are independent from one another one of hydrogen, an        aliphatic group with a main chain having 1 to about 20 carbon        atoms, an alicyclic group, an aromatic group, an arylaliphatic        group and an arylalicyclic group, comprising 0 to about 3        heteroatoms independently selected from the group consisting of        N, O, S, Se and Si.

-   7. The compound of clauses 5 or 6, wherein the metal M is selected    from the group consisting of Boron, Aluminum, Zinc, Tin, Titanium,    Zirconium, Indium, Copper, Iridium, and Lanthanum.

-   8. A compound of Formula (VI)

-   -   wherein R is one of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³,        —R⁴CONR⁵R⁶, —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂),        —R⁴C(O)C(R³)CR⁵R⁶ and —R⁴CO₂C(R³)O, wherein R³, R⁵ and R⁶ are        independent from one another one of hydrogen, an aliphatic group        with a main chain having 1 to about 20 carbon atoms, an        alicyclic group, an aromatic group, an arylaliphatic group and        an arylalicyclic group, comprising 0 to about 3 heteroatoms        independently selected from the group consisting of N, O, S, Se        and Si, R⁴ is one of an aliphatic bridge with a main chain        having 1 to about 20 carbon atoms, an alicyclic bridge, an        aromatic bridge, an arylaliphatic bridge and an arylalicyclic        bridge, comprising 0 to about 3 heteroatoms independently        selected from the group consisting of N, O, S, Se and Si, X is        halogen, and    -   R⁹ is alkyl.

-   9. A compound of Formula (IV)

-   -   wherein R is one of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³,        —R⁴CONR⁵R⁶, —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂),        —R⁴C(O)C(R³)CR⁵R⁶ and —R⁴CO₂C(R³)O, wherein R³, R⁵ and R⁶ are        independent from one another one of hydrogen, an aliphatic group        with a main chain having 1 to about 20 carbon atoms, an        alicyclic group, an aromatic group, an arylaliphatic group and        an arylalicyclic group, comprising 0 to about 3 heteroatoms        independently selected from the group consisting of N, O, S, Se        and Si, R⁴ is one of an aliphatic bridge with a main chain        having 1 to about 20 carbon atoms, an alicyclic bridge, an        aromatic bridge, an arylaliphatic bridge and an arylalicyclic        bridge, comprising 0 to about 3 heteroatoms independently        selected from the group consisting of N, O, S, Se and Si, X is        halogen,    -   Y is a nitrogen protecting group, and    -   R⁹ is alkyl.

-   10. The compound of clause 9, wherein Y is removable by    hydrogenolysis.

-   11. The compound of any one of clauses 3 to 10, wherein R⁹ is    (C₁-C₁₀) alkyl.

-   12. A compound of Formula (IVA)

-   -   wherein R is one of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³,        —R⁴CONR⁵R⁶, —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂),        —R⁴C(O)C(R³)CR⁵R⁶ and —R⁴CO₂C(R³)O,        -   wherein R³, R⁵ and R⁶ are independent from one another one            of hydrogen, an aliphatic group with a main chain having 1            to about 20 carbon atoms, an alicyclic group, an aromatic            group, an arylaliphatic group and an arylalicyclic group,            comprising 0 to about 3 heteroatoms independently selected            from the group consisting of N, O, S, Se and Si, R⁴ is one            of an aliphatic bridge with a main chain having 1 to about            20 carbon atoms, an alicyclic bridge, an aromatic bridge, an            arylaliphatic bridge and an arylalicyclic bridge, comprising            0 to about 3 heteroatoms independently selected from the            group consisting of N, O, S, Se and Si, X is halogen,    -   Y is a nitrogen protecting group, and    -   R¹⁰ is a protecting group that is removable in the presence of R        by hydrogenolysis.

-   13. The compound of clause 12, wherein Y is removable by    hydrogenolysis.

-   14. The compound of clauses 12 or 13, wherein R is aryl-methylenyl.

-   15. The compound of any one of clauses 9-14, wherein the nitrogen    protecting group Y is one of alkoxycarbonyl, benzhydryl,    trifluoroacetyl, t-butoxycarbonyl, a carbamate, an amide, a cyclic    imide, an N-Alkyl amine, an N-Aryl amine, an imine, and an enamine.

-   16. A compound of Formula (VIA)

-   -   wherein R is one of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³,        —R⁴CONR⁵R⁶, —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂),        —R⁴C(O)C(R³)CR⁵R⁶ and —R⁴CO₂C(R³)O, wherein R³, R⁵ and R⁶ are        independent from one another one of hydrogen, an aliphatic group        with a main chain having 1 to about 20 carbon atoms, an        alicyclic group, an aromatic group, an arylaliphatic group and        an arylalicyclic group, comprising 0 to about 3 heteroatoms        independently selected from the group consisting of N, O, S, Se        and Si, R⁴ is one of an aliphatic bridge with a main chain        having 1 to about 20 carbon atoms, an alicyclic bridge, an        aromatic bridge, an arylaliphatic bridge and an arylalicyclic        bridge, comprising 0 to about 3 heteroatoms independently        selected from the group consisting of N, O, S, Se and Si and X        is halogen.

-   17. A method of preparing a compound of Formula (VI)

-   -   wherein R is one of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³,        —R⁴CONR⁵R⁶, —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂),        —R⁴C(O)C(R³)CR⁵R⁶ and —R⁴CO₂C(R³)O, wherein R³, R⁵ and R⁶ are        independent from one another one of hydrogen, an aliphatic group        with a main chain having 1 to about 20 carbon atoms, an        alicyclic group, an aromatic group, an arylaliphatic group and        an arylalicyclic group, comprising 0 to about 3 heteroatoms        independently selected from the group consisting of N, O, S, Se        and Si, R⁴ is one of an aliphatic bridge with a main chain        having 1 to about 20 carbon atoms, an alicyclic bridge, an        aromatic bridge, an arylaliphatic bridge and an arylalicyclic        bridge, comprising 0 to about 3 heteroatoms independently        selected from the group consisting of N, O, S, Se and Si, X is        halogen, and    -   R⁹ is alkyl;    -   the method comprising providing a compound of Formula (IV)

-   -   wherein in Formula (IV)    -   R is one of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³, —R⁴CONR⁵R⁶,        —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂), —R⁴C(O)C(R³)CR⁵R⁶ and        —R⁴CO₂C(R³)O, wherein R³, R⁵ and R⁶ are independent from one        another one of hydrogen, an aliphatic group with a main chain        having 1 to about 20 carbon atoms, an alicyclic group, an        aromatic group, an arylaliphatic group and an arylalicyclic        group, comprising 0 to about 3 heteroatoms independently        selected from the group consisting of N, O, S, Se and Si, R⁴ is        one of an aliphatic bridge with a main chain having 1 to about        20 carbon atoms, an alicyclic bridge, an aromatic bridge, an        arylaliphatic bridge and an arylalicyclic bridge, comprising 0        to about 3 heteroatoms independently selected from the group        consisting of N, O, S, Se and Si, X is halogen,    -   Y is a nitrogen protecting group that is removable by        hydrogenolysis, and R⁹ is alkyl; and    -   exposing the compound of Formula (IV) to H₂ in the presence of a        Pd/C catalyst, thereby allowing the deprotection of the Na group        of compound (IV).

-   18. The method of clause 17, wherein providing the compound of    Formula (IV) comprises:    -   contacting a compound of Formula (III)

-   -   with an acyl halide RCOX in the presence of an alkali base,    -   wherein in Formula (III) Y is a nitrogen protecting group that        is removable by hydrogenolysis, and    -   R⁹ is alkyl.

19. A method of forming a compound of Formula (VIA)

-   -   wherein R is one of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³,        —R⁴CONR⁵R⁶, —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂),        —R⁴C(O)C(R³)CR⁵R⁶ and —R⁴CO₂C(R³)O, wherein R³, R⁵ and R⁶ are        independent from one another one of hydrogen, an aliphatic group        with a main chain having 1 to about 20 carbon atoms, an        alicyclic group, an aromatic group, an arylaliphatic group and        an arylalicyclic group, comprising 0 to about 3 heteroatoms        independently selected from the group consisting of N, O, S, Se        and Si, R⁴ is one of an aliphatic bridge with a main chain        having 1 to about 20 carbon atoms, an alicyclic bridge, an        aromatic bridge, an arylaliphatic bridge and an arylalicyclic        bridge, comprising 0 to about 3 heteroatoms independently        selected from the group consisting of N, O, S, Se and Si, and X        is halogen,    -   the method comprising providing a compound of Formula (IVA)

-   -   wherein in Formula (IVA)    -   R is one of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³, —R⁴CONR⁵R⁶,        —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂), —R⁴C(O)C(R³)CR⁵R⁶ and        —R⁴CO₂C(R³)O, wherein R³, R⁵ and R⁶ are independent from one        another one of hydrogen, an aliphatic group with a main chain        having 1 to about 20 carbon atoms, an alicyclic group, an        aromatic group, an arylaliphatic group and an arylalicyclic        group, comprising 0 to about 3 heteroatoms independently        selected from the group consisting of N, O, S, Se and Si, R⁴ is        one of an aliphatic bridge with a main chain having 1 to about        20 carbon atoms, an alicyclic bridge, an aromatic bridge, an        arylaliphatic bridge and an arylalicyclic bridge, comprising 0        to about 3 heteroatoms independently selected from the group        consisting of N, O, S, Se and Si, X is halogen,    -   Y is a nitrogen protecting group that is removable by        hydrogenolysis, and    -   R¹⁰ is a protecting group that is removable in the presence of R        by hydrogenolysis; and    -   exposing the compound of Formula (IVA) to H₂ in the presence of        a suitable catalyst, thereby (i) allowing the deprotection of        the Na group of compound (IVA) and (ii) allowing the cleavage of        the ester bond to moiety R¹⁰ of compound (IVA)

-   20. The method of clause 19, wherein R¹⁰ is aryl-methylenyl.

-   21. The method of clauses 19 or 20, wherein providing the compound    of Formula (IVA) comprises contacting a compound of Formula (IIIA)

-   -   with an acyl halide RCOX in the presence of an alkali base,    -   wherein in Formula (III) Y is a nitrogen protecting group that        is removable by hydrogenolysis, and    -   R¹⁰ is a protecting group that is removable in the presence of R        in a compound of Formula (IVA) by hydrogenolysis.

-   22. A method of preparing a compound of Formula (VII)

-   -   wherein R is one of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³,        —R⁴CONR⁵R⁶, —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂),        —R⁴C(O)C(R³)CR⁵R⁶ and —R⁴CO₂C(R³)O, wherein R³, R⁵ and R⁶ are        independent from one another one of hydrogen, an aliphatic group        with a main chain having 1 to about 20 carbon atoms, an        alicyclic group, an aromatic group, an arylaliphatic group and        an arylalicyclic group, comprising 0 to about 3 heteroatoms        independently selected from the group consisting of N, O, S, Se        and Si, R⁴ is one of an aliphatic bridge with a main chain        having 1 to about 20 carbon atoms, an alicyclic bridge, an        aromatic bridge, an arylaliphatic bridge and an arylalicyclic        bridge, comprising 0 to about 3 heteroatoms independently        selected from the group consisting of N, O, S, Se and Si, X is        halogen, and    -   R¹ and R² are independent from one another one of hydrogen, an        aliphatic group with a main chain having 1 to about 20 carbon        atoms, an alicyclic group, an aromatic group, an arylaliphatic        group and an arylalicyclic group, comprising 0 to about 3        heteroatoms independently selected from the group consisting of        N, O, S, Se and Si;    -   the method comprising reacting a compound of Formula (VI)

-   -   with a compound R¹MgX, R²MgX or a mixture of R¹MgX and R²MgX,        wherein R¹ and R² are independent from one another one of        hydrogen, an aliphatic group with a main chain having 1 to about        20 carbon atoms, an alicyclic group, an aromatic group, an        arylaliphatic group and an arylalicyclic group, comprising 0 to        about 3 heteroatoms independently selected from the group        consisting of N, O, S, Se and Si;    -   wherein in Formula VI,    -   R is one of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³, —R⁴CONR⁵R⁶,        —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂), —R⁴C(O)C(R³)CR⁵R⁶ and        —R⁴CO₂C(R³)O, wherein R³, R⁵ and R⁶ are independent from one        another one of hydrogen, an aliphatic group with a main chain        having 1 to about 20 carbon atoms, an alicyclic group, an        aromatic group, an arylaliphatic group and an arylalicyclic        group, comprising 0 to about 3 heteroatoms independently        selected from the group consisting of N, O, S, Se and Si, R⁴ is        one of an aliphatic bridge with a main chain having 1 to about        20 carbon atoms, an alicyclic bridge, an aromatic bridge, an        arylaliphatic bridge and an arylalicyclic bridge, comprising 0        to about 3 heteroatoms independently selected from the group        consisting of N, O, S, Se and Si, X is halogen, and    -   R⁹ is alkyl.

-   23. The method of clause 22, wherein R¹ and R² are identical.

-   24. A method of preparing a compound of Formula (IV)

-   -   wherein R is one of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³,        —R⁴CONR⁵R⁶, —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂),        —R⁴C(O)C(R³)CR⁵R⁶ and —R⁴CO₂C(R³)O, wherein R³, R⁵ and R⁶ are        independent from one another one of hydrogen, an aliphatic group        with a main chain having 1 to about 20 carbon atoms, an        alicyclic group, an aromatic group, an arylaliphatic group and        an arylalicyclic group, comprising 0 to about 3 heteroatoms        independently selected from the group consisting of N, O, S, Se        and Si, R⁴ is one of an aliphatic bridge with a main chain        having 1 to about 20 carbon atoms, an alicyclic bridge, an        aromatic bridge, an arylaliphatic bridge and an arylalicyclic        bridge, comprising 0 to about 3 heteroatoms independently        selected from the group consisting of N, O, S, Se and Si, X is        halogen,    -   Y is a nitrogen protecting group, and    -   R⁹ is alkyl;    -   the method comprising contacting a compound of Formula (III)

-   -   with an acyl halide RCOX in the presence of an alkali base,    -   wherein in Formula (III) Y is a nitrogen protecting group, and    -   R⁹ is alkyl.

-   25. A method of preparing a compound of Formula (IVA)

-   -   wherein R is one of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³,        —R⁴CONR⁵R⁶, —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂),        —R⁴C(O)C(R³)CR⁵R⁶ and —R⁴CO₂C(R³)O, wherein R³, R⁵ and R⁶ are        independent from one another one of hydrogen, an aliphatic group        with a main chain having 1 to about 20 carbon atoms, an        alicyclic group, an aromatic group, an arylaliphatic group and        an arylalicyclic group, comprising 0 to about 3 heteroatoms        independently selected from the group consisting of N, O, S, Se        and Si, R⁴ is one of an aliphatic bridge with a main chain        having 1 to about 20 carbon atoms, an alicyclic bridge, an        aromatic bridge, an arylaliphatic bridge and an arylalicyclic        bridge, comprising 0 to about 3 heteroatoms independently        selected from the group consisting of N, O, S, Se and Si, X is        halogen,    -   Y is a nitrogen protecting group, and    -   R¹⁰ is a protecting group that is removable in the presence of R        by hydrogenolysis;    -   the method comprising contacting a compound of Formula (IIIA)

-   -   with an acyl halide RCOX in the presence of an alkali base,    -   wherein in Formula (IIIA) Y is a nitrogen protecting group that        is removable by hydrogenolysis, and    -   R¹⁰ is a protecting group that is removable in the presence of R        by hydrogenolysis.

-   26. The method of clause 23, wherein R¹⁰ is aryl-methylenyl

-   27. The method of any of clauses 22 to 24, wherein the nitrogen    protecting group Y is one of alkoxycarbonyl, benzhydryl,    trifluoroacetyl, t-butoxycarbonyl, a carbamate, an amide, a cyclic    imide, an N-Alkyl amine, an N-Aryl amine, an imine, and an enamine.

-   28. The method of any of clauses 24 to 27, wherein the alkali base    is sodium carbonate.

-   29. The method of any one of the clauses 18, 21, 24 and 25, wherein    the compound of Formula (III) or the compound of Formula (IIIA) is    prepared by a process that comprises an acid catalyzed cyclization    of an Nα-protected-tryptophan alkyl ester.

-   30. The method of clause 29, wherein the Na-protected-tryptophan    alkyl ester is an Nα-alkoxycarbonyl-tryptophan alkyl ester.

-   31. A method of preparing a compound of Formula (VIII)

-   -   wherein M is a metal selected from the group consisting of Group        1 to Group 14 metals, lanthanides and actinides,    -   R is one of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³, —R⁴CONR⁵R⁶,        —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂), —R⁴C(O)C(R³)CR⁵R⁶ and        —R⁴CO₂C(R³)O,        -   wherein R³, R⁵ and R⁶ are independent from one another one            of hydrogen, an aliphatic group with a main chain having 1            to about 20 carbon atoms, an alicyclic group, an aromatic            group, an arylaliphatic group and an arylalicyclic group,            comprising 0 to about 3 heteroatoms independently selected            from the group consisting of N, O, S, Se and Si, R⁴ is one            of an aliphatic bridge with a main chain having 1 to about            20 carbon atoms, an alicyclic bridge, an aromatic bridge, an            arylaliphatic bridge and an arylalicyclic bridge, comprising            0 to about 3 heteroatoms independently selected from the            group consisting of N, O, S, Se and Si, X is halogen, and    -   R¹ and R² are independent from one another one of hydrogen, an        aliphatic group with a main chain having 1 to about 20 carbon        atoms, an alicyclic group, an aromatic group, an arylaliphatic        group and an arylalicyclic group, comprising 0 to about 3        heteroatoms independently selected from the group consisting of        N, O, S, Se and Si;    -   the method comprising reacting a compound of Formula (VII)

-   -   with a metal compound selected from the group consisting of        Group 1 to Group 14 metals, lanthanides and actinides,    -   wherein in Formula VII    -   R is one of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³, —R⁴CONR⁵R⁶,        —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂), —R⁴C(O)C(R³)CR⁵R⁶ and        —R⁴CO₂C(R³)O,        -   wherein R³, R⁵ and R⁶ are independent from one another one            of hydrogen, an aliphatic group with a main chain having 1            to about 20 carbon atoms, an alicyclic group, an aromatic            group, an arylaliphatic group and an arylalicyclic group,            comprising 0 to about 3 heteroatoms independently selected            from the group consisting of N, O, S, Se and Si, R⁴ is one            of an aliphatic bridge with a main chain having 1 to about            20 carbon atoms, an alicyclic bridge, an aromatic bridge, an            arylaliphatic bridge and an arylalicyclic bridge, comprising            0 to about 3 heteroatoms independently selected from the            group consisting of N, O, S, Se and Si, X is halogen, and    -   R¹ and R² are independent from one another one of hydrogen, an        aliphatic group with a main chain having 1 to about 20 carbon        atoms, an alicyclic group, an aromatic group, an arylaliphatic        group and an arylalicyclic group, comprising 0 to about 3        heteroatoms independently selected from the group consisting of        N, O, S, Se and Si.

-   32. A method of preparing a compound of Formula (IX)

-   -   wherein M is a metal selected from the group consisting of Group        1 to Group 14 metals, lanthanides and actinides,    -   R is one of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³, —R⁴CONR⁵R⁶,        —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂), —R⁴C(O)C(R³)CR⁵R⁶ and        —R⁴CO₂C(R³)O,        -   wherein R³, R⁵ and R⁶ are independent from one another one            of hydrogen, an aliphatic group with a main chain having 1            to about 20 carbon atoms, an alicyclic group, an aromatic            group, an arylaliphatic group and an arylalicyclic group,            comprising 0 to about 3 heteroatoms independently selected            from the group consisting of N, O, S, Se and Si, R⁴ is one            of an aliphatic bridge with a main chain having 1 to about            20 carbon atoms, an alicyclic bridge, an aromatic bridge, an            arylaliphatic bridge and an arylalicyclic bridge, comprising            0 to about 3 heteroatoms independently selected from the            group consisting of N, O, S, Se and Si, X is halogen, and    -   R¹ and R² are independent from one another one of hydrogen, an        aliphatic group with a main chain having 1 to about 20 carbon        atoms, an alicyclic group, an aromatic group, an arylaliphatic        group and an arylalicyclic group, comprising 0 to about 3        heteroatoms independently selected from the group consisting of        N, O, S, Se and Si;    -   the method comprising reacting a compound of Formula (VII)

-   -   with a metal compound selected from the group consisting of        Group 1 to Group 14 metals, lanthanides and actinides,    -   wherein in Formula VII        -   R is one of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³, —R⁴CONR⁵R⁶,            —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂), —R⁴C(O)C(R³)CR⁵R⁶            and —R⁴CO₂C(R³)O, wherein R³, R⁵ and R⁶ are independent from            one another one of hydrogen, an aliphatic group with a main            chain having 1 to about 20 carbon atoms, an alicyclic group,            an aromatic group, an arylaliphatic group and an            arylalicyclic group, comprising 0 to about 3 heteroatoms            independently selected from the group consisting of N, O, S,            Se and Si, R⁴ is one of an aliphatic bridge with a main            chain having 1 to about 20 carbon atoms, an alicyclic            bridge, an aromatic bridge, an arylaliphatic bridge and an            arylalicyclic bridge, comprising 0 to about 3 heteroatoms            independently selected from the group consisting of N, O, S,            Se and Si, X is halogen, and        -   R¹ and R² are independent from one another one of hydrogen,            an aliphatic group with a main chain having 1 to about 20            carbon atoms, an alicyclic group, an aromatic group, an            arylaliphatic group and an arylalicyclic group, comprising 0            to about 3 heteroatoms independently selected from the group            consisting of N, O, S, Se and Si.

-   33. The method of clauses 31 or 32, wherein the metal compound M is    selected from the group consisting of BH₃, B₂H₆, B₅H₉, B₁₀H₁₄,    AlCl₃, ZnCl₂, Zn(OTf)₂, ZnEt₂, SnCl₂, TiCl₄, Ti(Oi-Pr)₄, Cp₂TiCl₂,    ZrCl₄, Cp₂ZrCl₂, InCl₃, In(OTf)₃, Cu(OAc)₂, (IrCp*Cl₂)₂,    (Ir(COD)Cl)₂, LnCl₃, and LnCp₂Cl₂.

-   34. The use of the compound of any one of clauses 1 to 9, 15 and 16    as a ligand for asymmetric catalysis.

-   35. The use of clause 34, wherein the compound is one of clauses 3    to 9 or 12, as a ligand for asymmetric reduction of a ketone.

-   36. The use of clause 34, wherein the compound is a compound of    clause 13, as a ligand for the asymmetric formation of a covalent    bond in a Michael addition.

-   37. The use of clause 36, further comprising the use of a basic    cocatalyst.

-   38. The use of clauses 36 or 37, wherein the Michael addition is    carried out in an alcohol solvent or in an aqueous phase.

-   39. The use of any one of clauses 36-38, wherein the Michael donor    in the Michael addition is an aldehyde.

-   40. The use of any one of clauses 36-39, wherein the Michael    acceptor in the Michael addition is a nitro group or a sulphonyl    group.

What is claimed is:
 1. A compound of Formula (VIII)

the compound having a bowl-shaped conformation, wherein M is a metalselected from the group consisting of Group 1 to Group 14 metals,lanthanides and actinides, wherein R is one of —COOR³, —R⁴COOR³, —R⁴CHO,—R⁴COR³, —R⁴CONR⁵R⁶, —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂),—R⁴C(O)C(R³)CR⁵R⁶ and R⁴CO₂C(R³)O, wherein R³, R⁵ and R⁶ are independentfrom one another one of hydrogen, an aliphatic group with a main chainhaving 1 to about 20 carbon atoms, an alicyclic group, an aromaticgroup, an arylaliphatic group and an arylalicyclic group, comprising 0to about 3 heteroatoms independently selected from the group consistingof N, O, S, Se and Si, R⁴ is one of an aliphatic bridge with a mainchain having 1 to about 20 carbon atoms, an alicyclic bridge, anaromatic bridge, an arylaliphatic bridge and an arylalicyclic bridge,comprising 0 to about 3 heteroatoms independently selected from thegroup consisting of N, O, S, Se and Si, X is halogen, and R¹ and R² areindependent from one another one of hydrogen, an aliphatic group with amain chain having 1 to about 20 carbon atoms, an alicyclic group, anaromatic group, an arylaliphatic group and an arylalicyclic group,comprising 0 to about 3 heteroatoms independently selected from thegroup consisting of N, O, S, Se and Si.
 2. A compound of Formula (IX)

the compound having an S-shaped conformation, wherein M is a metalselected from the group consisting of Group 1 to Group 14 metals,lanthanides and actinides, R is one of —COOR³, —R⁴COOR³, —R⁴CHO,—R⁴COR³, —R⁴CONR⁵R⁶, —R⁴COX, —R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂),—R⁴C(O)C(R³)CR⁵R⁶ and —R⁴CO₂C(R³)O, wherein R³, R⁵ and R⁶ areindependent from one another one of hydrogen, an aliphatic group with amain chain having 1 to about 20 carbon atoms, an alicyclic group, anaromatic group, an arylaliphatic group and an arylalicyclic group,comprising 0 to about 3 heteroatoms independently selected from thegroup consisting of N, O, S, Se and Si, R⁴ is one of an aliphatic bridgewith a main chain having 1 to about 20 carbon atoms, an alicyclicbridge, an aromatic bridge, an arylaliphatic bridge and an arylalicyclicbridge, comprising 0 to about 3 heteroatoms independently selected fromthe group consisting of N, O, S, Se and Si, X is halogen, and R¹ and R²are independent from one another one of hydrogen, an aliphatic groupwith a main chain having 1 to about 20 carbon atoms, an alicyclic group,an aromatic group, an arylaliphatic group and an arylalicyclic group,comprising 0 to about 3 heteroatoms independently selected from thegroup consisting of N, O, S, Se and Si.
 3. The compound of claim 1,wherein the metal M is selected from the group consisting of Boron,Aluminum, Zinc, Tin, Titanium, Zirconium, Indium, Copper, Iridium, andLanthanum.
 4. The compound of claim 2, wherein the metal M is selectedfrom the group consisting of Boron, Aluminum, Zinc, Tin, Titanium,Zirconium, Indium, Copper, Iridium, and Lanthanum.
 5. A method ofpreparing a compound of Formula (VIII)

wherein M is a metal selected from the group consisting of Group 1 toGroup 14 metals, lanthanides and actinides, R is one of —COOR³,—R⁴COOR³, —R⁴CHO, —R⁴COR³, —R⁴CONR⁵R⁶, —R⁴COX, —R⁴OP(═O)(OH)₂,—R⁴P(═O)(OH)₂), —R⁴C(O)C(R³)CR⁵R⁶ and —R⁴CO₂C(R³)O, wherein R³, R⁵ andR⁶ are independent from one another one of hydrogen, an aliphatic groupwith a main chain having 1 to about 20 carbon atoms, an alicyclic group,an aromatic group, an arylaliphatic group and an arylalicyclic group,comprising 0 to about 3 heteroatoms independently selected from thegroup consisting of N, O, S, Se and Si, R⁴ is one of an aliphatic bridgewith a main chain having 1 to about 20 carbon atoms, an alicyclicbridge, an aromatic bridge, an arylaliphatic bridge and an arylalicyclicbridge, comprising 0 to about 3 heteroatoms independently selected fromthe group consisting of N, O, S, Se and Si, X is halogen, and R¹ and R²are independent from one another one of hydrogen, an aliphatic groupwith a main chain having 1 to about 20 carbon atoms, an alicyclic group,an aromatic group, an arylaliphatic group and an arylalicyclic group,comprising 0 to about 3 heteroatoms independently selected from thegroup consisting of N, O, S, Se and Si; the method comprising reacting acompound of Formula (VII)

with a metal compound selected from the group consisting of Group 1 toGroup 14 metals, lanthanides and actinides, wherein in Formula VII R isone of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³, —R⁴CONR⁵R⁶, —R⁴COX,—R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂), —R⁴C(O)C(R³)CR⁵R⁶ and —R⁴CO₂C(R³)O,wherein R³, R⁵ and R⁶ are independent from one another one of hydrogen,an aliphatic group with a main chain having 1 to about 20 carbon atoms,an alicyclic group, an aromatic group, an arylaliphatic group and anarylalicyclic group, comprising 0 to about 3 heteroatoms independentlyselected from the group consisting of N, O, S, Se and Si, R⁴ is one ofan aliphatic bridge with a main chain having 1 to about 20 carbon atoms,an alicyclic bridge, an aromatic bridge, an arylaliphatic bridge and anarylalicyclic bridge, comprising 0 to about 3 heteroatoms independentlyselected from the group consisting of N, O, S, Se and Si, X is halogen,and R¹ and R² are independent from one another one of hydrogen, analiphatic group with a main chain having 1 to about 20 carbon atoms, analicyclic group, an aromatic group, an arylaliphatic group and anarylalicyclic group, comprising 0 to about 3 heteroatoms independentlyselected from the group consisting of N, O, S, Se and Si.
 6. A method ofpreparing a compound of Formula (IX)

wherein M is a metal selected from the group consisting of Group 1 toGroup 14 metals, lanthanides and actinides, R is one of —COOR³,—R⁴COOR³, —R⁴CHO, —R⁴COR³, —R⁴CONR⁵R⁶, —R⁴COX, —R⁴OP(═O)(OH)₂,—R⁴P(═O)(OH)₂), —R⁴C(O)C(R³)CR⁵R⁶ and —R⁴CO₂C(R³)O, wherein R³, R⁵ andR⁶ are independent from one another one of hydrogen, an aliphatic groupwith a main chain having 1 to about 20 carbon atoms, an alicyclic group,an aromatic group, an arylaliphatic group and an arylalicyclic group,comprising 0 to about 3 heteroatoms independently selected from thegroup consisting of N, O, S, Se and Si, R⁴ is one of an aliphatic bridgewith a main chain having 1 to about 20 carbon atoms, an alicyclicbridge, an aromatic bridge, an arylaliphatic bridge and an arylalicyclicbridge, comprising 0 to about 3 heteroatoms independently selected fromthe group consisting of N, O, S, Se and Si, X is halogen, and R¹ and R²are independent from one another one of hydrogen, an aliphatic groupwith a main chain having 1 to about 20 carbon atoms, an alicyclic group,an aromatic group, an arylaliphatic group and an arylalicyclic group,comprising 0 to about 3 heteroatoms independently selected from thegroup consisting of N, O, S, Se and Si; the method comprising reacting acompound of Formula (VII)

with a metal compound selected from the group consisting of Group 1 toGroup 14 metals, lanthanides and actinides, wherein in Formula VII R isone of —COOR³, —R⁴COOR³, —R⁴CHO, —R⁴COR³, —R⁴CONR⁵R⁶, —R⁴COX,—R⁴OP(═O)(OH)₂, —R⁴P(═O)(OH)₂), —R⁴C(O)C(R³)CR⁵R⁶ and —R⁴CO₂C(R³)O,wherein R³, R⁵ and R⁶ are independent from one another one of hydrogen,an aliphatic group with a main chain having 1 to about 20 carbon atoms,an alicyclic group, an aromatic group, an arylaliphatic group and anarylalicyclic group, comprising 0 to about 3 heteroatoms independentlyselected from the group consisting of N, O, S, Se and Si, R⁴ is one ofan aliphatic bridge with a main chain having 1 to about 20 carbon atoms,an alicyclic bridge, an aromatic bridge, an arylaliphatic bridge and anarylalicyclic bridge, comprising 0 to about 3 heteroatoms independentlyselected from the group consisting of N, O, S, Se and Si, X is halogen,and R¹ and R² are independent from one another one of hydrogen, analiphatic group with a main chain having 1 to about 20 carbon atoms, analicyclic group, an aromatic group, an arylaliphatic group and anarylalicyclic group, comprising 0 to about 3 heteroatoms independentlyselected from the group consisting of N, O, S, Se and Si.
 7. The methodof claim 5, wherein the metal compound M is selected from the groupconsisting of BH₃, B₂H₆, B₅H₉, B₁₀H₁₄, AlCl₃, ZnCl₂, Zn(OTf)₂, ZnEt₂,SnCl₂, TiCl₄, Ti(Oi-Pr)₄, Cp₂TiCl₂, ZrCl₄, Cp₂ZrCl₂, InCl₃, In(OTf)₃,Cu(OAc)₂, (IrCp*Cl₂)₂, (Ir(COD)Cl)₂, LnCl₃, and LnCp₂Cl₂.
 8. The methodof claim 6, wherein the metal compound M is selected from the groupconsisting of BH₃, B₂H₆, B₅H₉, B₁₀H₁₄, AlCl₃, ZnCl₂, Zn(OTf)₂, ZnEt₂,SnCl₂, TiCl₄, Ti(Oi-Pr)₄, Cp₂TiCl₂, ZrCl₄, Cp₂ZrCl₂, InCl₃, In(OTf)₃,Cu(OAc)₂, (IrCp*Cl₂)₂, (Ir(COD)Cl)₂, LnCl₃, and LnCp₂Cl₂.